Genetic continuity and change among the Indigenous peoples of California.

Before the colonial period, California harboured more language variation than all of Europe, and linguistic and archaeological analyses have led to many hypotheses to explain this diversity1. We report genome-wide data from 79 ancient individuals from California and 40 ancient individuals from Northern Mexico dating to 7,400-200 years before present (BP). Our analyses document long-term genetic continuity between people living on the Northern Channel Islands of California and the adjacent Santa Barbara mainland coast from 7,400 years BP to modern Chumash groups represented by individuals who lived around 200 years BP. The distinctive genetic lineages that characterize present-day and ancient people from Northwest Mexico increased in frequency in Southern and Central California by 5,200 years BP, providing evidence for northward migrations that are candidates for spreading Uto-Aztecan languages before the dispersal of maize agriculture from Mexico2-4. Individuals from Baja California share more alleles with the earliest individual from Central California in the dataset than with later individuals from Central California, potentially reflecting an earlier linguistic substrate, whose impact on local ancestry was diluted by later migrations from inland regions1,5. After 1,600 years BP, ancient individuals from the Channel Islands lived in communities with effective sizes similar to those in pre-agricultural Caribbean and Patagonia, and smaller than those on the California mainland and in sampled regions of Mexico.

Historic and bioarchaeological evidence supports late onset of post-Columbian epidemics in Native California.

Catastrophic decline of Indigenous populations in the Americas following European contact is one of the most severe demographic events in the history of humanity, but uncertainty persists about the timing and scale of the collapse, which has implications for not only Indigenous history but also the understanding of historical ecology. A long-standing hypothesis that a continent-wide pandemic broke out immediately upon the arrival of Spanish seafarers has been challenged in recent years by a model of regional epidemics erupting asynchronously, causing different rates of population decline in different areas. Some researchers have suggested that, in California, significant depopulation occurred during the first two centuries of the post-Columbus era, which led to a "rebound" in native flora and fauna by the time of sustained European contact after 1769. Here, we combine a comprehensive prehistoric osteological dataset (n = 10,256 individuals) with historic mission mortuary records (n = 23,459 individuals) that together span from 3050 cal BC to AD 1870 to systematically evaluate changes in mortality over time by constructing life tables and conducting survival analysis of age-at-death records. Results show that a dramatic shift in the shape of mortality risk consistent with a plague-like population structure began only after sustained contact with European invaders, when permanent Spanish settlements and missions were established ca. AD 1770. These declines reflect the syndemic effects of newly introduced diseases and the severe cultural disruption of Indigenous lifeways by the Spanish colonial system.

Bayesian chronological analyses consistent with synchronous age of 12,835-12,735 Cal B.P. for Younger Dryas boundary on four continents.

The Younger Dryas impact hypothesis posits that a cosmic impact across much of the Northern Hemisphere deposited the Younger Dryas boundary (YDB) layer, containing peak abundances in a variable assemblage of proxies, including magnetic and glassy impact-related spherules, high-temperature minerals and melt glass, nanodiamonds, carbon spherules, aciniform carbon, platinum, and osmium. Bayesian chronological modeling was applied to 354 dates from 23 stratigraphic sections in 12 countries on four continents to establish a modeled YDB age range for this event of 12,835-12,735 Cal B.P. at 95% probability. This range overlaps that of a peak in extraterrestrial platinum in the Greenland Ice Sheet and of the earliest age of the Younger Dryas climate episode in six proxy records, suggesting a causal connection between the YDB impact event and the Younger Dryas. Two statistical tests indicate that both modeled and unmodeled ages in the 30 records are consistent with synchronous deposition of the YDB layer within the limits of dating uncertainty (∼ 100 y). The widespread distribution of the YDB layer suggests that it may serve as a datum layer.

Sociopolitical effects of bow and arrow technology in prehistoric coastal California.

Bow and arrow technology spread across California between ∼AD 250 and 1200, first appearing in the intermountain deserts of the Great Basin and later spreading to the coast. We critically evaluate the available data for the initial spread in bow and arrow technology and examine its societal effects on the well-studied Northern Channel Islands off the coast of Southern California. The introduction of this technology to these islands between AD 650 and 900 appears to predate the appearance of hereditary inequality between AD 900 and 1300. We conclude, based on the available data, that this technology did not immediately trigger intergroup warfare. We argue that the introduction of the bow and arrow contributed to sociopolitical instabilities that were on the rise within the context of increasing population levels and unstable climatic conditions, which stimulated intergroup conflict and favored the development of hereditary inequality. Population aggregation and economic intensification did occur with the introduction of the bow and arrow. This observation is consistent with the hypothesis that social coercion via intra-group "law enforcement" contributed to changes in societal scale that ultimately resulted in larger groups that were favored in inter-group conflict. We argue that the interplay between intra-group "law enforcement" and inter-group warfare were both essential for the ultimate emergence of social inequality between AD 900 and 1300.

Approval summary: imatinib mesylate for one or three years in the adjuvant treatment of gastrointestinal stromal tumors.

On January 31, 2012, the U.S. Food and Drug Administration granted regular approval of imatinib mesylate tablets (Gleevec®; Novartis Pharmaceuticals Corporation, East Hanover, NJ) for the adjuvant treatment of adult patients following complete gross resection of Kit(+) (CD117(+)) gastrointestinal stromal tumors (GISTs). The recommended dose of imatinib is 400 mg/day administered daily for 3 years. Three hundred ninety-seven patients were enrolled in a randomized adjuvant, multicenter, open label, phase III trial comparing 12 months with 36 months of imatinib treatment. Eligible patients had one of the following: tumor diameter >5 cm and mitotic count >5 per 50 high power fields (HPFs); tumor diameter >10 cm and any mitotic count; tumor of any size with mitotic count >10/50 HPFs; or tumor ruptured into the peritoneal cavity. The primary endpoint was the recurrence-free survival (RFS) interval. The median follow-up for patients without an RFS event was 42 months. There were 84 (42%) RFS events in the 12-month treatment arm and 50 (25%) RFS events in the 36-month treatment arm. Thirty-six months of imatinib treatment led to a significantly longer RFS interval than with 12 months of treatment. The median follow-up for overall survival (OS) evaluation in patients still living was 48 months. Thirty-six months of imatinib treatment led to a significantly longer OS time than with 12 months of imatinib treatment. The most common adverse reactions, as noted in previous imatinib studies, were diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain.

Shock-synthesized hexagonal diamonds in Younger Dryas boundary sediments.

The long-standing controversy regarding the late Pleistocene megafaunal extinctions in North America has been invigorated by a hypothesis implicating a cosmic impact at the Allerød-Younger Dryas boundary or YDB (approximately 12,900 +/- 100 cal BP or 10,900 +/- 100 (14)C years). Abrupt ecosystem disruption caused by this event may have triggered the megafaunal extinctions, along with reductions in other animal populations, including humans. The hypothesis remains controversial due to absence of shocked minerals, tektites, and impact craters. Here, we report the presence of shock-synthesized hexagonal nanodiamonds (lonsdaleite) in YDB sediments dating to approximately 12,950 +/- 50 cal BP at Arlington Canyon, Santa Rosa Island, California. Lonsdaleite is known on Earth only in meteorites and impact craters, and its presence strongly supports a cosmic impact event, further strengthened by its co-occurrence with other nanometer-sized diamond polymorphs (n-diamonds and cubics). These shock-synthesized diamonds are also associated with proxies indicating major biomass burning (charcoal, carbon spherules, and soot). This biomass burning at the Younger Dryas (YD) onset is regional in extent, based on evidence from adjacent Santa Barbara Basin and coeval with broader continent-wide biomass burning. Biomass burning also coincides with abrupt sediment mass wasting and ecological disruption and the last known occurrence of pygmy mammoths (Mammuthus exilis) on the Channel Islands, correlating with broader animal extinctions throughout North America. The only previously known co-occurrence of nanodiamonds, soot, and extinction is the Cretaceous-Tertiary (K/T) impact layer. These data are consistent with abrupt ecosystem change and megafaunal extinction possibly triggered by a cosmic impact over North America at approximately 12,900 +/- 100 cal BP.

Approval summary: letrozole (Femara® tablets) for adjuvant and extended adjuvant postmenopausal breast cancer treatment: conversion of accelerated to full approval.

On April 30, 2010, the U.S. Food and Drug Administration converted letrozole (Femara®; Novartis Pharmaceuticals Corporation, East Hanover, NJ) from accelerated to full approval for adjuvant and extended adjuvant (following 5 years of tamoxifen) treatment of postmenopausal women with hormone receptor-positive early breast cancer. The initial accelerated approvals of letrozole for adjuvant and extended adjuvant treatment on December 28, 2005 and October 29, 2004, respectively, were based on an analysis of the disease-free survival (DFS) outcome of patients followed for medians of 26 months and 28 months, respectively. Both trials were double-blind, multicenter studies. Both trials were unblinded early when an interim analysis showed a favorable letrozole effect on DFS. In updated intention-to-treat analyses of both trials, the risk for a DFS event was lower with letrozole than with tamoxifen (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.77-0.99; p = .03) in the adjuvant trial and was lower than with placebo (HR, 0.89; 95% CI, 0.76-1.03; p = .12) in the extended adjuvant trial. The latter analysis ignores the interim switch of 60% of placebo-treated patients to letrozole. Bone fractures and osteoporosis were reported more frequently following treatment with letrozole whereas tamoxifen was associated with a higher risk for endometrial proliferation and endometrial cancer. Myocardial infarction was more frequently reported with letrozole than with tamoxifen, but the incidence of thromboembolic events was higher with tamoxifen than with letrozole. Lipid-lowering medications were required for 25% of patients on letrozole and 16% of patients on tamoxifen.

Approval summary: erlotinib maintenance therapy of advanced/metastatic non-small cell lung cancer (NSCLC).

On April 16, 2010, the U. S. Food and Drug Administration (FDA) approved erlotinib tablets (Tarceva®; OSI Pharmaceuticals, Inc., Melville, NY) for maintenance treatment of patients with stage IIIB/IV non-small cell lung cancer (NSCLC) whose disease had not progressed after four cycles of platinum-based first-line chemotherapy. In total, 889 patients received either erlotinib (150 mg) or placebo once daily. Progression-free survival (PFS), in all patients and in patients with epidermal growth factor receptor (EGFR)(+) tumors by immunohistochemistry (IHC), was the primary efficacy endpoint. Overall survival (OS) was a secondary sponsor endpoint but was the primary regulatory endpoint. Median PFS times were 2.8 months and 2.6 months in the erlotinib and placebo arms, respectively (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.62-0.82; p < .001). Median OS times were 12.0 months and 11.0 months, favoring erlotinib (HR, 0.81; 95% CI, 0.70-0.95). The PFS and OS HRs in patients with EGFR(+) tumors by IHC were 0.69 (95% CI, 0.58-0.82) and 0.77 (95% CI, 0.64-0.93), respectively. The PFS and OS HRs in patients with EGFR(-) tumors by IHC were 0.77 (95% CI, 0.51-1.14) and 0.91 (95% CI, 0.59-1.38), respectively. Following disease progression, 57% of placebo-treated patients received additional chemotherapy, compared with 47% of erlotinib-treated patients. Fourteen percent of placebo-treated patients received erlotinib or gefitinib, 31% received docetaxel, and 14% received pemetrexed. In total, 59% of placebo-treated patients who received treatment received FDA approved second-line NSCLC drugs. The most common adverse reactions in patients receiving erlotinib were rash and diarrhea.

Vorinostat for treatment of cutaneous manifestations of advanced primary cutaneous T-cell lymphoma.

PURPOSE: To discuss vorinostat approval for treatment of cutaneous manifestations of advanced cutaneous T-cell lymphoma (CTCL). EXPERIMENTAL DESIGN: Data from 1 single-arm, open-label, multicenter pivotal trial and 11 other trials submitted to support the new drug application for vorinostat in the treatment of advanced primary CTCL were reviewed. The pivotal trial assessed responses by changes in overall skin disease score using a severity-weighted assessment tool (SWAT). Vorinostat could be considered active in CTCL if observed response rate was at least 20% and the lower bound of the corresponding 95% confidence interval (95% CI) excluded 5%. Patients reported pruritus relief using a questionnaire and a visual analogue scale. RESULTS: The pivotal trial enrolled 74 patients with stage IB or higher CTCL. Median number of prior treatments was 3, and 61 patients (82%) had stage IIB or higher disease. The objective response rate in the skin disease assessed by change in the overall SWAT score from the baseline was 30% (95% CI, 18.5 to 42.6) in patients with stage IIB or higher disease. Median response duration (end of response defined by 50% increase in SWAT score from the nadir) was 168 days. Median time to tumor progression was 148 days for overall population and 169 days for patients with stage IIB or higher disease. Assessment of pruritus relief was considered unreliable. CONCLUSIONS: Vorinostat showed activity in CTCL, and skin responses were a clinical benefit. Vorinostat was approved for treatment of cutaneous manifestations of CTCL. A nonblinded, single-arm trial did not allow a reliable assessment of pruritus relief.

The perioperative cost of Infuse bone graft in posterolateral lumbar spine fusion.

BACKGROUND CONTEXT: There is mounting evidence supporting the efficacy of bone morphogenetic protein (BMP) for both anterior interbody and posterolateral lumbar fusion. However, the relative cost of BMP remains an important concern for physicians, hospitals, and payers. PURPOSE: The purpose of this study is to report on the perioperative costs for patients treated with rhBMP-2 as compared with an iliac crest bone graft (ICBG) supplemented with graft extenders. STUDY DESIGN/SETTING: A prospective randomized controlled trial of rhBMP-2/ACS (Infuse Bone Graft; Medtronic Sofamor Danek, Memphis, TN) versus ICBG+/-graft extender for lumbar spine fusion in patients over 60 years old. PATIENT SAMPLE: One hundred two patients over 60 years old who required a posterolateral lumbar spine fusion randomized between receiving rhBMP-2/ACS or ICBG. OUTCOME MEASURES: All health-care costs over the first 3 months after surgery. METHODS: As part of a prospective randomized trial of rhBMP-2/ACS versus ICBG+/-graft extender for lumbar spine fusion, all costs over the first 3 months after surgery were directly recorded by a dedicated coder funded by Norton Healthcare, Louisville, KY. A dedicated research nurse also followed all patients throughout their hospital stay and posthospitalization recovery to identify any adverse events or additional outpatient medical care. RESULTS: Fifty patients received rhBMP-2/ACS and 52 underwent ICBG harvest. The mean hospital cost for the index admission was $24,736 for the rhBMP-2/ACS group and $21,138 for the ICBG group. Mean inpatient physician costs were $5,082 in the rhBMP-2/ACS group and $5,316 in the ICBG group. Costs associated with posthospital rehabilitation averaged $4,906 in the rhBMP-2/ACS group versus $6,820 in the ICBG group. Total payer expenditure for the 3-month perioperative period averaged $33,860 in the rhBMP-2/ACS group and $37,227 in the ICBG group. CONCLUSIONS: The hospital carries the cost burden associated with the utilization of rhBMP-2/ACS. In contrast, the payer in a Diagnosis-Related Group (DRG) model achieves a net savings, based primarily on the decreased payment for inpatient rehabilitation, but also on decreased hospital reimbursement, physician costs, and other outpatient services.

Orthopaedic in-training examination performance: a nine-year review of a residency program database.

BACKGROUND: The Orthopaedic In-Training Examination (OITE) provides an objective way for both the residency program and the resident to monitor progress. METHODS: This longitudinal descriptive study tracks the OITE performance of 16 residents from one orthopaedic surgery residency program over nine years (1997-2005). Domain comparisons are made to national averages (N > 3000) by mean difference and split middle celeration line assessment trend analysis to evaluate program strengths and weaknesses. Further evaluation by postgraduate year (PGY) is made of domains that were deemed to be in need of moderate attention. RESULTS: Resident performance for the medically related issues, rehabilitation, and sports medicine domains were deemed acceptable. Resident performance on the orthopaedic science, orthopaedic diseases, hip and knee reconstruction, spine, and shoulder and elbow domains were deemed to be in need of minor attention. Musculoskeletal trauma, pediatric orthopaedics, foot and ankle, and hand domains were deemed to be in need of moderate attention. Further analysis of these domains by PGY revealed less positive slopes for the pediatric orthopaedics and musculoskeletal trauma domains, and a negative slope for the hand domain between PGY-3 and PGY-4, each indicative of lower domain-specific OITE scores than the national mean. A similar, less positive slope was identified between PGY-2 and PGY-3 for the foot and ankle domain. CONCLUSIONS: A longitudinal descriptive review of orthopaedic surgery resident OITE performance enables the departmental education committee to identify curricular content areas that require attention, select the most efficient modes of educational information delivery, facilitate learning through the application of innovative educational technologies, establish measurable educational program goals, and more prescriptively allocate personnel and equipment resources.

Sagittal alignment as a risk factor for adjacent level degeneration: a case-control study.

This study examined whether sagittal alignment, preexisting adjacent level degeneration, and smoking predispose patients to adjacent segment degeneration following lumbar fusion. Fifty-one patients with adjacent segment degeneration were identified and matched with control patients based on age, sex, level, and date of index surgery. Preexisting adjacent level degeneration and sagittal alignment through the fusion and from L1-S1 were determined before and after initial surgery. Patients with adjacent segment degeneration had significantly less lordosis through the fusion and lumbar spine following their initial surgery. There was no significant difference in the amount of preexisting adjacent level degeneration and smoking between the adjacent segment degeneration and control groups. Fusion of the lumbar spine in abnormal sagittal alignment, with loss of lumbar lordosis, predisposes patients to the development of adjacent segment degeneration. Adjacent segment degeneration does not appear to be just a progression of preexisting degenerative changes at the adjacent level.

The effect of storage temperature on blue cheese mechanical properties.

Blue cheese is commonly aged for 60 days at 10°C after curing. However, some manufacturers store blue cheese at 4°C and the effect of lower storage temperature on blue cheese final properties is unknown. Thus, the objective of this study was to determine the effect of storage temperature and time on blue cheese mechanical behaviors. Blue cheeses were stored at 4 or 10°C for 77 days after production. Composition and small- and large-strain rheological behaviors were evaluated every 2 weeks of storage. Storage time had significant impact on blue cheese rheological behaviors; storage temperature did not. Large-strain compressive force and viscoelastic moduli decreased with storage time, and the extent of nonlinear viscoelastic behavior increased. These results indicated that sample microstructure likely weakened and was more easily deformed as storage time increased. Overall, blue cheese can be stored at 4-10°C without significant changes to its composition or mechanical behavior. PRACTICAL APPLICATIONS: The results of this work can be used by blue cheese manufacturers to better understand the impact of storage time and temperature on blue cheese end quality. Manufacturers can take advantage of the effects of storage time on blue cheese mechanical behaviors to determine how long to age blue cheese to achieve the desired texture.

The evolution of partial undercutting facetectomy in the treatment of lumbar spinal stenosis.

Decompression of lumbar spinal stenosis is the most common spinal surgery in those over 60 years of age. While this procedure has shown immediate and durable benefits, improvements in outcome have not changed significantly. Technical aspects of surgical decompression have evolved significantly. The recently introduced ultrasonic bone cutter allows a precise and safe peri-neural bone resection. The principles of preservation of stability, as described by Getty et al. have remained as relevant as when these were described 40 years ago.

Ancient human parallel lineages within North America contributed to a coastal expansion.

Little is known regarding the first people to enter the Americas and their genetic legacy. Genomic analysis of the oldest human remains from the Americas showed a direct relationship between a Clovis-related ancestral population and all modern Central and South Americans as well as a deep split separating them from North Americans in Canada. We present 91 ancient human genomes from California and Southwestern Ontario and demonstrate the existence of two distinct ancestries in North America, which possibly split south of the ice sheets. A contribution from both of these ancestral populations is found in all modern Central and South Americans. The proportions of these two ancestries in ancient and modern populations are consistent with a coastal dispersal and multiple admixture events.

The role of SN-38 exposure, UGT1A1*28 polymorphism, and baseline bilirubin level in predicting severe irinotecan toxicity.

Irinotecan, an anticancer drug, is associated with severe and potentially fatal diarrhea and neutropenia. The objective of this analysis was to evaluate the role of SN-38 exposure, the active metabolite of irinotecan, UGT1A1 genotypes, and baseline bilirubin on the maximum decrease (nadir) in absolute neutrophil counts following irinotecan. This analysis extended the work of a previous study that examined the effect of UGT1A1 genotypes on the incidence of severe neutropenia in 86 advanced cancer patients following irinotecan treatment. Regression analysis showed that the absolute neutrophil count nadir depended on SN-38 exposure (AUC) and UGT1A1*28 homozygous 7/7 genotype. An increased SN-38 AUC and the 7/7 genotype were significantly associated with a lower absolute neutrophil count nadir (R2 = .49). An alternate model suggested that higher baseline bilirubin and the 7/7 genotype were also significantly associated with a lower absolute neutrophil count nadir, although with a lower coefficient of determination (R2 = .31). Based on these findings and other reports, the irinotecan label was modified to indicate the role of UGT1A1*28 polymorphism in the metabolism of irinotecan and the associated increased risk of severe neutropenia. The label modifications also included recommendations for lower starting doses of irinotecan in patients homozygous for the UGT1A1*28 (7/7) polymorphism.

Erlotinib/gemcitabine for first-line treatment of locally advanced or metastatic adenocarcinoma of the pancreas.

Erlotinib (Tarceva) is a human epidermal growth factor receptor type 1/epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor initially approved by the US Food and Drug Administration for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer after failure of at least one prior chemotherapy regimen. In this report, we present the pivotal study that led to the approval of erlotinib in combination with gemcitabine (Gemzar) in patients with locally advanced/metastatic chemonaive pancreatic cancer patients. The combination demonstrated a statistically significant increase in overall survival accompanied by an increase in toxicity. Physicians and patients now have a new option for the treatment of locally advanced/metastatic adenocarcinoma of the pancreas.

Approval summary: nelarabine for the treatment of T-cell lymphoblastic leukemia/lymphoma.

PURPOSE: To describe the clinical studies, chemistry manufacturing and controls, and clinical pharmacology and toxicology that led to Food and Drug Administration approval of nelarabine (Arranon) for the treatment of T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma. EXPERIMENTAL DESIGN: Two phase 2 trials, one conducted in pediatric patients and the other in adult patients, were reviewed. The i.v. dose and schedule of nelarabine in the pediatric and adult studies was 650 mg/m2/d daily for 5 days and 1,500 mg/m2 on days 1, 3, and 5, respectively. Treatments were repeated every 21 days. Study end points were the rates of complete response (CR) and CR with incomplete hematologic or bone marrow recovery (CR*). RESULTS: The pediatric efficacy population consisted of 39 patients who had relapsed or had been refractory to two or more induction regimens. CR to nelarabine treatment was observed in 5 (13%) patients and CR+CR* was observed in 9 (23%) patients. The adult efficacy population consisted of 28 patients. CR to nelarabine treatment was observed in 5 (18%) patients and CR+CR* was observed in 6 (21%) patients. Neurologic toxicity was dose limiting for both pediatric and adult patients. Other severe toxicities included laboratory abnormalities in pediatric patients and gastrointestinal and pulmonary toxicities in adults. CONCLUSIONS: On October 28, 2005, the Food and Drug Administration granted accelerated approval for nelarabine for treatment of patients with relapsed or refractory T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma after at least two prior regimens. This use is based on the induction of CRs. The applicant will conduct postmarketing clinical trials to show clinical benefit (e.g., survival prolongation).