A Case With Twists and Turns: A Report of Vertebrobasilar Dolichoectasia.

Vertebrobasilar dolichoectasia (VBD) is a rare anatomical abnormality of the vertebral artery system, defined as irregular expansion, elongation, and tortuosity of vertebral arteries. Anomalies of the vertebrobasilar artery can have a wide variety of clinical presentations, ranging from simple headaches to debilitating strokes. We present the case of an atypical presentation of VBD which mimicked trigeminal neuralgia by compressing the trigeminal nerve. There are currently no guidelines concerning the management of VBD, nor is there evidence of a definitive cure. This case invoked discussions among the medical team as to whether management should be medically or surgically focused, as well as long-term outcomes for patients with VBD. The superiority of medical versus surgical treatment of this issue is still a debated topic. This patient trialed medical management with dexamethasone and carbamazepine with no improvement in symptoms. He then underwent surgical gamma knife treatment but even this invasive measure was unsuccessful at relieving his symptoms. We hope that by presenting this case, we can display how the therapies available for VBD are limited and often unsuccessful in relieving the disease burden in patients with VBD.

Gonorrheal and chlamydia yield for genital and extragenital testing in children evaluated for sexual abuse.

OBJECTIVE: Texas Forensic Nurse Examiners (TXFNE) performs routine testing of genital and non-genital sites for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG), and further testing for other sexually transmitted pathogens. The current Centers for Disease Control and Prevention (CDC) guidelines recommend that testing be based primarily on patient history of type of sexual contact, patient age, community prevalence of sexually transmitted infections (STIs), perpetrator risk factors for STIs, and patient symptoms (Centers for Disease Control and Prevention, 2021). In this study, we were interested in determining whether our practice of testing all sites in all prepubertal patients presenting for sexual abuse for CT and NG resulted in identification of infections that would have been missed if testing had been limited to disclosed sites of sexual contact. METHODS: We conducted a retrospective chart review of all children younger than 14 years who presented to a clinical or hospital site for evaluation by TXFNE in Harris County or surrounding counties during the period January 2020-December 2021. RESULTS: Of the 675 patients tested, 61 patients (9 %) had genital injuries and 45 patients (7 %) had either reported symptoms or examination findings consistent with possible STI infection. There were 11 patients who had positive gonorrhea and/or chlamydia results. Of the 11 patients with a positive result, 10 patients' reported history of type of contact did not fully match sites that tested positive. Diagnosis of STI infection would have been missed for 5 patients if testing had been limited to the disclosed sites of sexual contact. CONCLUSION: Positive results for CT and NG at undisclosed body sites in children presenting with concern for sexual abuse most likely represent infection from sexual contact. Limiting STI testing based on disclosed contact may lead to missed NG and CT infections in prepubertal patients with concern for sexual abuse. This can lead to delayed treatment of the infection and a missed opportunity to ensure the safety of the child.

To Transfuse or Not to Transfuse: A Case of Unresectable Renal Cell Carcinoma-Induced Warm Autoimmune Hemolytic Anemia.

Warm autoimmune hemolytic anemia (WAIHA) is a rare disease. Roughly half of all cases are considered either primary or idiopathic. The remaining cases are typically secondary to a drug reaction or an underlying disease state such as malignancy, infection, or chronic autoimmune disease. Treatments for WAIHA include corticosteroids, intravenous immunoglobulin (IVIG), rituximab, and splenectomy. We present a case of WAIHA with underlying clear cell renal cell carcinoma (RCC) that was unresectable, creating a difficult treatment course. A 76-year-old male with recently diagnosed clear cell RCC was admitted with symptomatic WAIHA and significant hemodynamic instability. Over the course of his admission, he received 25 blood transfusions, erythropoietin, methylprednisolone, IVIG, rituximab, and mycophenolate mofetil in an attempt to control his disease state. He suffered end-organ damage in the form of heart failure with reduced ejection fraction. He was deemed too unstable for RCC resection or interventional cardiac procedures. Determining an appropriate transfusion threshold proved to be a noteworthy challenge. His hemoglobin eventually stabilized to 7.4 g/dL upon discharge over the course of 27 days of treatment. The underlying cause of his WAIHA was believed to be most likely secondary to RCC. WAIHA may have a prolonged treatment course with high risk of mortality if the underlying cause is not resolvable. If this is the case, it can be difficult to determine a hemoglobin transfusion threshold that maintains normal vital signs while minimizing the risk of transfusion-associated circulatory overload (TACO) and transfusion-related acute lung injury (TRALI). Prolonged hemodynamic instability may result in end-organ damage. For our patient, we aimed for a hemoglobin transfusion threshold of 5.0-6.0 g/dL based on his mean arterial pressure (MAP), heart rate, and subjective symptoms.

A role for fibroblast-derived SASP factors in the activation of pyroptotic cell death in mammary epithelial cells.

In normal tissue homeostasis, bidirectional communication between different cell types can shape numerous biological outcomes. Many studies have documented instances of reciprocal communication between fibroblasts and cancer cells that functionally change cancer cell behavior. However, less is known about how these heterotypic interactions shape epithelial cell function in the absence of oncogenic transformation. Furthermore, fibroblasts are prone to undergo senescence, which is typified by an irreversible cell cycle arrest. Senescent fibroblasts are also known to secrete various cytokines into the extracellular space; a phenomenon that is termed the senescence-associated secretory phenotype (SASP). While the role of fibroblast-derived SASP factors on cancer cells has been well studied, the impact of these factors on normal epithelial cells remains poorly understood. We discovered that treatment of normal mammary epithelial cells with conditioned media from senescent fibroblasts (SASP CM) results in a caspase-dependent cell death. This capacity of SASP CM to cause cell death is maintained across multiple senescence-inducing stimuli. However, the activation of oncogenic signaling in mammary epithelial cells mitigates the ability of SASP CM to induce cell death. Despite the reliance of this cell death on caspase activation, we discovered that SASP CM does not cause cell death by the extrinsic or intrinsic apoptotic pathway. Instead, these cells die by an NLRP3, caspase-1, and gasdermin D-dependent induction of pyroptosis. Taken together, our findings reveal that senescent fibroblasts can cause pyroptosis in neighboring mammary epithelial cells, which has implications for therapeutic strategies that perturb the behavior of senescent cells.

A role for fibroblast-derived SASP factors in the activation of pyroptotic cell death in mammary epithelial cells.

In normal tissue homeostasis, bidirectional communication between different cell types can shape numerous biological outcomes. Many studies have documented instances of reciprocal communication between fibroblasts and cancer cells that functionally change cancer cell behavior. However, less is known about how these heterotypic interactions shape epithelial cell function in the absence of oncogenic transformation. Furthermore, fibroblasts are prone to undergo senescence, which is typified by an irreversible cell cycle arrest. Senescent fibroblasts are also known to secrete various cytokines into the extracellular space; a phenomenon that is termed the senescence-associated secretory phenotype (SASP). While the role of fibroblast derived SASP factors on cancer cells has been well studied, the impact of these factors on normal epithelial cells remains poorly understood. We discovered that treatment of normal mammary epithelial cells with conditioned media (CM) from senescent fibroblasts (SASP CM) results in a caspase-dependent cell death. This capacity of SASP CM to cause cell death is maintained across multiple senescence-inducing stimuli. However, the activation of oncogenic signaling in mammary epithelial cells mitigates the ability of SASP CM to induce cell death. Despite the reliance of this cell death on caspase activation, we discovered that SASP CM does not cause cell death by the extrinsic or intrinsic apoptotic pathway. Instead, these cells die by an NLRP3, caspase-1, and gasdermin D (GSDMD)-dependent induction of pyroptosis. Taken together, our findings reveal that senescent fibroblasts can cause pyroptosis in neighboring mammary epithelial cells, which has implications for therapeutic strategies that perturb the behavior of senescent cells.

Cross-Reactive SARS-CoV-2 Neutralizing Antibodies From Deep Mining of Early Patient Responses.

Passive immunization using monoclonal antibodies will play a vital role in the fight against COVID-19. The recent emergence of viral variants with reduced sensitivity to some current antibodies and vaccines highlights the importance of broad cross-reactivity. This study describes deep-mining of the antibody repertoires of hospitalized COVID-19 patients using phage display technology and B cell receptor (BCR) repertoire sequencing to isolate neutralizing antibodies and gain insights into the early antibody response. This comprehensive discovery approach has yielded a panel of potent neutralizing antibodies which bind distinct viral epitopes including epitopes conserved in SARS-CoV-1. Structural determination of a non-ACE2 receptor blocking antibody reveals a previously undescribed binding epitope, which is unlikely to be affected by the mutations in any of the recently reported major viral variants including B.1.1.7 (from the UK), B.1.351 (from South Africa) and B.1.1.28 (from Brazil). Finally, by combining sequences of the RBD binding and neutralizing antibodies with the B cell receptor repertoire sequencing, we also describe a highly convergent early antibody response. Similar IgM-derived sequences occur within this study group and also within patient responses described by multiple independent studies published previously.

Implementation of a comprehensive intervention focused on hospitalized patients with HIV by an existing stewardship program: successes and lessons learned.

BACKGROUND: Several national organizations have advocated for inpatient antiretroviral stewardship to prevent the consequences of medication-related errors. This study aimed to evaluate the impact of a stewardship initiative on outcomes in people with HIV (PWH). METHODS: A pharmacist-led audit and review of adult patients admitted with an ICD-10 code for HIV was implemented to an existing antimicrobial stewardship program. A quasi-experimental, retrospective cohort study was conducted comparing PWH admitted during pre- and post-intervention periods. Rates of antiretroviral therapy (ART)-related errors and infectious diseases (ID) consultation with linkage to care were evaluated through selection of a random sample of patients receiving ART in each period. Length of stay (LOS) and mortality were assessed by analyzing all admissions in the post-intervention period. Clinical outcomes including LOS, 30-day all-cause hospital readmission, and in-hospital and 30-day mortality in the post-intervention group were stratified by patients not on ART, on ART at admission, and started on ART as a result of the intervention. RESULTS: A total of 100 patients in the pre-intervention period and 103 patients in the post-intervention period were included to assess ART-related errors and linkage to care. A reduction in errors (70.0 versus 25.7%, p < 0.001) and increased linkage to care (19.0 versus 39.6%, p < 0.01) were demonstrated. Of 389 admissions during the post-intervention period, 30-day mortality rates were similar between PWH on ART at admission and those initiated on ART during admission (5% versus 8%, respectively), but less than those not on ART (21%). A longer LOS was observed in the patients started on ART during admission (5 days if ART started during admission versus 3 days if not started during admission, p < 0.01). CONCLUSIONS: This interdisciplinary intervention was successful in reducing inpatient ART-related errors and increasing ID consultation with linkage to care among PWH.

Reading direction and spatial effects in parity and arithmetic tasks.

This study investigated the relationship between numerical and spatial processing and reading direction, conducting conceptual replications of the Shaki et al. (Psychonomic Bulletin & Review 16(2): 328-331, 2009) parity task and the Mathieu et al. (Cognition 146: 229-239, 2016, Experiment 1) simple addition (e.g., 3 + 2) and subtraction (e.g., 3 - 2) task. Twenty-four left-to-right readers (LTR) and 24 right-to-left readers (RTL) were tested. The response time (RT) analysis of the parity task presented a robust spatial-numerical association of response codes (SNARC) effect (left-side response advantage for smaller numbers and right-side advantage for larger numbers) for LTR but not RTL readers. In the arithmetic task, the three problem elements (e.g., 3 + 4) were presented sequentially with the second operand displaced slightly to the left or right of fixation. RTL but not LTR readers presented a RT advantage for subtraction relative to addition with a right-shifted second operand compared to it being left-shifted. This is consistent with a spatial bias linked to native reading direction. For both reading-direction groups, effects of the left vs. right side manipulation in the arithmetic or parity task did not correspond to parallel effects in the other task. The results imply that the parity-based SNARC effects and side-related effects in cognitive arithmetic are not equivalent measures of space-related processes in cognitive number processing and likely reflect distinct mechanisms.

An Antibody Targeting ICOS Increases Intratumoral Cytotoxic to Regulatory T-cell Ratio and Induces Tumor Regression.

The immunosuppressive tumor microenvironment constitutes a significant hurdle to immune checkpoint inhibitor responses. Both soluble factors and specialized immune cells, such as regulatory T cells (Treg), are key components of active intratumoral immunosuppression. Inducible costimulatory receptor (ICOS) can be highly expressed in the tumor microenvironment, especially on immunosuppressive Treg, suggesting that it represents a relevant target for preferential depletion of these cells. Here, we performed immune profiling of samples from tumor-bearing mice and patients with cancer to demonstrate differential expression of ICOS in immune T-cell subsets in different tissues. ICOS expression was higher on intratumoral Treg than on effector CD8 T cells. In addition, by immunizing an Icos knockout transgenic mouse line expressing antibodies with human variable domains, we selected a fully human IgG1 antibody called KY1044 that bound ICOS from different species. We showed that KY1044 induced sustained depletion of ICOShigh T cells but was also associated with increased secretion of proinflammatory cytokines from ICOSlow effector T cells (Teff). In syngeneic mouse tumor models, KY1044 depleted ICOShigh Treg and increased the intratumoral TEff:Treg ratio, resulting in increased secretion of IFNγ and TNFα by TEff cells. KY1044 demonstrated monotherapy antitumor efficacy and improved anti-PD-L1 efficacy. In summary, we demonstrated that using KY1044, one can exploit the differential expression of ICOS on T-cell subtypes to improve the intratumoral immune contexture and restore an antitumor immune response.

What is learned in procedural learning? The case of alphabet arithmetic.

This research pursued a fine-grained analysis of the acquisition of a procedural skill. In two experiments (n = 29 and n = 27), adults practiced 12 alphabet arithmetic problems (e.g., C + 3 = C D E F) in two sessions with 20 practice blocks in each. If learning reflected speed up of a counting algorithm, response time (RT) speed up should be proportional to the number of counting steps (+ 1, + 2, or + 3). Instead, we found about 50% of RT gains occurred in the first six blocks of practice during which speed up was parallel for + 1, + 2, and + 3 problems. In both experiments, RT initially was a linear function of addend size, reflecting a letter counting strategy. Mean RT for + 3 problems was eventually equal to + 2 problems, which suggests that speed up reflected a gradual shift to associative fact retrieval. Trial by trial strategy self-reports in Experiment 2 revealed that the proportion of trials reported as memory retrieval as opposed to counting predicted 96% of the variance in RT as a function of addend size and practice block. As such, the results provided no evidence for speed up of a counting algorithm and indicated that skill acquisition for this task entailed speed up of task-general processes independent of addend size and rapid transition from counting to fact retrieval. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Evidence for a retrieval over a sum counting theory of adults' simple addition.

Researchers have recently proposed that educated adults solve the simplest addition problems (e.g., 3 + 2) by an automatic counting procedure, challenging the long-held view that educated adults solve small additions by associative memory retrieval. We tested predications of a sum-counting model that assumes a procedure in which the 2 quantities represented by the operands are encoded and counted sequentially. Here, we presented the 2 operands sequentially (e.g., "3 +" first and then "2") and manipulated the preview time for the first operand (O1) and operator across 2 experiments (both n = 36); the O1 preview times were 1000 ms and 500 ms in Experiments 1 and 2, respectively. We measured response time (RT) from the presentation of the second operand (O2) and compared it with RT when both operands appeared simultaneously. Contrary to the sum-counting model, with sequential presentation, problems with the same O2 sizes (e.g., 3 + 2, 4 + 2) demonstrated significant RT differences across levels of O1, and the sum of the operands was a better RT predictor than O2 with both sequential and simultaneous displays. These results challenge a sum-counting model of the present data but are consistent with a memory retrieval theory. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Does the min-counting strategy for simple addition become automatized in educated adults? A behavioural and ERP study of the size congruency effect.

Recent studies have proposed that the sum-counting strategy for simple addition (i.e., count up of the summed value of the two operands one by one) used at early age becomes automatized in adults, challenging the long held view that skilled adults solve simple addition problems by fact retrieval. As arithmetic skill develops, however, the sum-counting strategy usually is replaced by a more advanced and efficient min-counting strategy (i.e., start counting at the value of the larger addend and count up by ones equal to the smaller or "min" addend). Thus, one would expect the min strategy, rather than the sum strategy, to become automatized if we assume automatic counting procedures exist. The present study sought evidence of the min-strategy in adults by investigating the size congruency effect (SCE) through behavioural and event related brain potential (ERP) experiments. The SCE is observed in number comparison tasks (e.g., identify the larger of two numbers), where RT is slower when the physical and numerical size of the numbers are incongruent compared to when they are congruent. The min-counting strategy inherently requires a number comparison stage, because the min and max number must be determined before the counting begins. Experiment 1 tested 72 participants on addition and number comparison tasks. The results showed a robust behavioural SCE for number comparison but not for simple addition. Experiment 2 tested 20 participants with a large number of addition and number comparison problems and recorded ERP. The behavioural results replicated the findings of Experiment 1. The ERP results revealed brain signatures in line with previous studies and the current behavioural findings. No SCE indicated the absence of a number comparison stage for addition; thus, the present findings ruled out the possibility of a fast min-counting strategy, or more generally a min strategy, for adults' simple addition.

Haplosaurus computes protein haplotypes for use in precision drug design.

Selecting the most appropriate protein sequences is critical for precision drug design. Here we describe Haplosaurus, a bioinformatic tool for computation of protein haplotypes. Haplosaurus computes protein haplotypes from pre-existing chromosomally-phased genomic variation data. Integration into the Ensembl resource provides rapid and detailed protein haplotypes retrieval. Using Haplosaurus, we build a database of unique protein haplotypes from the 1000 Genomes dataset reflecting real-world protein sequence variability and their prevalence. For one in seven genes, their most common protein haplotype differs from the reference sequence and a similar number differs on their most common haplotype between human populations. Three case studies show how knowledge of the range of commonly encountered protein forms predicted in populations leads to insights into therapeutic efficacy. Haplosaurus and its associated database is expected to find broad applications in many disciplines using protein sequences and particularly impactful for therapeutics design.

NALCN Dysfunction as a Cause of Disordered Respiratory Rhythm With Central Apnea.

The sodium leak channel nonselective protein (NALCN) is a regulator of the pacemaker neurons that are responsible for rhythmic behavior (including respiration), maintaining the resting membrane potential, and are required for action potential production. NALCN-null mice show early death associated with disrupted respiratory rhythms, characterized by frequent and profound apneas. We report 3 children (2 siblings) with compound heterozygous mutations in NALCN associated with developmental impairment, hypotonia, and central sleep-disordered breathing causing apneas. Supplemental oxygen normalized the respiratory rhythm. NALCN mutations have been previously reported to cause severe hypotonia, speech impairment, and cognitive delay as well as infantile neuroaxonal dystrophy and facial dysmorphism. Nonsynonymous changes in the 2 affected extracellular loops may be responsible for the deleterious effect on the stability of the respiratory rhythm. Although oxygen is known to be a stabilizer of respiratory rhythm in central apnea in children, its role in NALCN dysfunction requires further investigation.

Transfer of training in simple addition.

In recent years, several researchers have proposed that skilled adults may solve single-digit addition problems (e.g., 3 + 1 = 4, 4 + 3 = 7) using a fast counting procedure. Practicing a procedure often leads to transfer of learning and faster performance of unpracticed items. Such transfer has been demonstrated using a counting-based alphabet arithmetic task (e.g., B + 4 = C D E F) that indicated robust generalization of practice (i.e., response time [RT] gains) when untrained transfer problems at test had been implicitly practiced (e.g., practice B + 3, test B + 2 or B + 1). Here, we constructed analogous simple addition problems (practice 4 + 3, test 4 + 2 or 4 + 1). In each of three experiments (total n = 108), participants received six practice blocks followed by two test blocks of new problems to examine generalization effects. Practice of addition identity rule problems (i.e., 0 + N = N) showed complete transfer of RT gains made during practice to unpracticed items at test. In contrast, the addition ties (2 + 2, 3 + 3, etc.) presented large RT costs for unpracticed problems at test, but sped up substantially in the second test block. This pattern is consistent with item-specific strengthening of associative memory. The critical items were small non-tie additions (sum ≤ 10) for which the test problems would be implicitly practiced if counting was employed during practice. In all three experiments (and collectively), there was no evidence of generalization for these items in the first test block, but there was robust speed up when the items were repeated in the second test block. Thus, there was no evidence of the generalization of practice that would be expected if counting procedures mediated our participants' performance on small non-tie addition problems.

In a Genomic Era, Placental Pathology Still Holds the Key in the Nondysmorphic Stillbirth.

Objective To explore the relative utility of genetic testing in contrast to placental pathology in explaining causation of death in the structurally normal stillborn population. Methods A retrospective review of a structurally normal stillborn infant cohort in South East Scotland between 2011 and 2015, defined by death at or after 24 weeks of gestation. We reviewed pathology reports and collected demographic data on cases. This information was collated with genetic test results (quantitative fluorescent polymerase chain reaction and microarray analysis) and placental pathology to create a database for analysis. Primary Results Within the structurally normal population (n = 131), there were 125 genetic tests performed and 11 abnormal results. Sixty-six microarray analyses were performed, and 2 (3%) of the results were thought likely to reflect cause of stillbirth (1 case of incomplete trisomy 4 and 1 case of deletion of chromosome Xp in a female). Analysis was significantly limited in 2 cases as parental samples were not available. The placental pathology was available in a total of 129 cases; significant findings were identified in 100 cases; 79 (61%) showed changes that were considered to have caused death (including cord "accidents"), and a further 21 (16%) showed findings likely to influence the management of subsequent pregnancies. Conclusions We reaffirm the utility of placental examination in the investigation of stillbirth. In cases of nondysmorphic stillbirth where placental pathology does not explain the cause of stillbirth, microarray analysis of fetal DNA can add further diagnostic information in 3% of cases but can add further diagnostic confusion, and it is important that parental bloods are taken to minimize this risk.

"Compacted" procedures for adults' simple addition: A review and critique of the evidence.

We review recent empirical findings and arguments proffered as evidence that educated adults solve elementary addition problems (3 + 2, 4 + 1) using so-called compacted procedures (e.g., unconscious, automatic counting); a conclusion that could have significant pedagogical implications. We begin with the large-sample experiment reported by Uittenhove, Thevenot and Barrouillet (2016, Cognition, 146, 289-303), which tested 90 adults on the 81 single-digit addition problems from 1 + 1 to 9 + 9. They identified the 12 very-small addition problems with different operands both ≤ 4 (e.g., 4 + 3) as a distinct subgroup of problems solved by unconscious, automatic counting: These items yielded a near-perfectly linear increase in answer response time (RT) yoked to the sum of the operands. Using the data reported in the article, however, we show that there are clear violations of the sum-counting model's predictions among the very-small addition problems, and that there is no real RT boundary associated with addends ≤4. Furthermore, we show that a well-known associative retrieval model of addition facts-the network interference theory (Campbell, 1995)-predicts the results observed for these problems with high precision. We also review the other types of evidence adduced for the compacted procedure theory of simple addition and conclude that these findings are unconvincing in their own right and only distantly consistent with automatic counting. We conclude that the cumulative evidence for fast compacted procedures for adults' simple addition does not justify revision of the long-standing assumption that direct memory retrieval is ultimately the most efficient process of simple addition for nonzero problems, let alone sufficient to recommend significant changes to basic addition pedagogy.

Pulmonary pharmacodynamics of an anti-GM-CSFRα antibody enables therapeutic dosing that limits exposure in the lung.

Pulmonary alveolar proteinosis is associated with impaired alveolar macrophage differentiation due to genetic defects in the granulocyte macrophage colony-stimulating factor (GM-CSF) axis or autoantibody blockade of GM-CSF. The anti-GM-CSFRα antibody mavrilimumab has shown clinical benefit in patients with rheumatoid arthritis, but with no accompanying pulmonary pathology observed to date. We aimed to model systemic versus pulmonary pharmacodynamics of an anti-GM-CSFRα antibody to understand the pharmacology that contributes to this therapeutic margin. Mice were dosed intraperitoneal with anti-GM-CSFRα antibody, and pharmacodynamics bioassays for GM-CSFRα inhibition performed on blood and bronchoalveolar lavage (BAL) cells to quantify coverage in the circulation and lung, respectively. A single dose of 3 mg/kg of the anti-GM-CSFRα antibody saturated the systemic cellular pool, but dosing up to 10 times higher had no effect on the responsiveness of BAL cells to GM-CSF. Continued administration of this dose of anti-GM-CSFRα antibody for 7 consecutive days also had no inhibitory effect on these cells. Partial inhibition of GM-CSFRα function on cells from the BAL was only observed after dosing for 5 or 7 consecutive days at 30 mg/kg, 10-fold higher than the proposed therapeutic dose. In conclusion, dosing with anti-GM-CSFRα antibody using regimes that saturate circulating cells, and have been shown to be efficacious in inflammatory arthritis models, did not lead to complete blockade of the alveolar macrophages response to GM-CSF. This suggests a significant therapeutic window is possible with GM-CSF axis inhibition.

Transfer of training in alphabet arithmetic.

In recent years, several researchers have proposed that skilled adults may solve single-digit addition problems (e.g., 3 + 1 = 4, 4 + 3 = 7) using a fast counting procedure. Practicing a procedure, however, often leads to transfer of learning to unpracticed items; consequently, the fast counting theory was potentially challenged by subsequent studies that found no generalization of practice for simple addition. In two experiments reported here (Ns = 48), we examined generalization in an alphabet arithmetic task (e.g., B + 5 = C D E F G) to determine that counting-based procedures do produce generalization. Both experiments showed robust generalization (i.e., faster response times relative to control problems) when a test problem's letter augend and answer letter sequence overlapped with practiced problems (e.g., practice B + 5 = C D E F G, test B + 3 = C D E ). In Experiment 2, test items with an unpracticed letter but whose answer was in a practiced letter sequence (e.g., practice C + 3 = DEF, test D + 2 = E F) also displayed generalization. Reanalysis of previously published addition generalization experiments (combined n = 172) found no evidence of facilitation when problems were preceded by problems with a matching augend and counting sequence. The clear presence of generalization in counting-based alphabet arithmetic, and the absence of generalization of practice effects in genuine addition, represent a challenge to fast counting theories of skilled adults' simple addition.