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.

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 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.

Posterior reversible encephalopathy syndrome following a thoracic discectomy-induced dural leak: case report.

Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiological syndrome characterized by headaches, altered mental status, seizures, and visual disturbances. Classic MRI findings include white matter changes of the parieto-occipital regions. This syndrome has been encountered in myriad medical illnesses, including hypertension, preeclampsia/eclampsia, and immunosuppressive conditions. While the pathogenesis of the disorder is unclear, vasoconstriction and hypoperfusion leading to brain ischemia and vasogenic edema have been implicated as potential mechanisms. The authors present, to the best of their knowledge, the first case of PRES following a thoracic spinal surgery-induced dural leak noted on resection of the fifth rib during a thoracotomy for a T4-5 discectomy. Brain MRI revealed large areas of increased FLAIR and T2 hyperintensity in the superior posterior frontal lobes, superior and medial parietal lobes, and bilateral occipital lobes. Following repair of the CSF leak, the patient's symptoms resolved. Spinal surgeons should be alert to the potentially life-threatening condition of PRES, especially in a hypertensive patient who experiences surgery-induced dural leakage. The development of a severe positional headache with neurological signs is a red flag that suggests the presence of PRES. Prompt attention to the diagnosis and treatment of this condition by repairing the dural leak via surgery or expeditious blood patch increases the likelihood of a favorable outcome.

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.

FDA approval summary: vemurafenib for treatment of unresectable or metastatic melanoma with the BRAFV600E mutation.

On August 17, 2011, the U.S. Food and Drug Administration (FDA) approved vemurafenib tablets (Zelboraf, Hoffmann-LaRoche Inc.) for the treatment of patients with unresectable or metastatic melanoma with the BRAF(V600E) mutation as detected by an FDA-approved test. The cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems, Inc.) was approved concurrently. An international, multicenter, randomized, open-label trial in 675 previously untreated patients with BRAF(V600E) mutation-positive unresectable or metastatic melanoma allocated 337 patients to receive vemurafenib, 960 mg orally twice daily, and 338 patients to receive dacarbazine, 1,000 mg/m(2) intravenously every 3 weeks. Overall survival was significantly improved in patients receiving vemurafenib [HR, 0.44; 95% confidence interval (CI), 0.33-0.59; P < 0.0001]. Progression-free survival was also significantly improved in patients receiving vemurafenib (HR, 0.26; 95% CI, 0.20-0.33; P < 0.0001). Overall response rates were 48.4% and 5.5% in the vemurafenib and dacarbazine arms, respectively. The most common adverse reactions (≥30%) in patients treated with vemurafenib were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, and nausea. Cutaneous squamous cell carcinomas or keratoacanthomas were detected in approximately 24% of patients treated with vemurafenib. Other adverse reactions included hypersensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, uveitis, QT prolongation, and liver enzyme laboratory abnormalities.

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.

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.

Accelerated approval of oncology products: the food and drug administration experience.

We reviewed the regulatory history of the accelerated approval process and the US Food and Drug Administration (FDA) experience with accelerated approval of oncology products from its initiation in December 11, 1992, to July 1, 2010. The accelerated approval regulations allowed accelerated approval of products to treat serious or life-threatening diseases based on surrogate endpoints that are reasonably likely to predict clinical benefit. Failure to complete postapproval trials to confirm clinical benefit with due diligence could result in removal of the accelerated approval indication from the market. From December 11, 1992, to July 1, 2010, the FDA granted accelerated approval to 35 oncology products for 47 new indications. Clinical benefit was confirmed in postapproval trials for 26 of the 47 new indications, resulting in conversion to regular approval. The median time between accelerated approval and regular approval of oncology products was 3.9 years (range = 0.8-12.6 years) and the mean time was 4.7 years, representing a substantial time savings in terms of earlier availability of drugs to cancer patients. Three new indications did not show clinical benefit when confirmatory postapproval trials were completed and were subsequently removed from the market or had restricted distribution plans implemented. Confirmatory trials were not completed for 14 new indications. The five longest intervals from receipt of accelerated approval to July 1, 2010, without completion of trials to confirm clinical benefit were 10.5, 6.4, 5.5, 5.5, and 4.7 years. The five longest intervals between accelerated approval and successful conversion to regular approval were 12.6, 9.7, 8.1, 7.5, and 7.4 years. Trials to confirm clinical benefit should be part of the drug development plan and should be in progress at the time of an application seeking accelerated approval to prevent an ineffective drug from remaining on the market for an unacceptable time.

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.

Relationship among United States Medical Licensing Step I, orthopedic in-training, subjective clinical performance evaluations, and american board of orthopedic surgery examination scores: a 12-year review of an orthopedic surgery residency program.

OBJECTIVE: To improve the understanding of relationships among United States Medical Licensing Examination (USMLE Step I), Orthopedic In-Training Examination (OITE), Subjective Clinical Performance Evaluations, and American Board of Orthopedic Surgery Examination Part I (Abos-I) and Part II (Abos-II), which would help residency programs better achieve their educational mission. DESIGN: A 12-year descriptive study of retrospectively collected data. SETTING: One residency program with 47 resident participants. RESULTS: Residents that failed Abos-I and Abos-II had lower program mean OITE year-in-training (YIT) percentile rank scores. The program mean OITE YIT percentile rank score had a moderate relationship with Abos-I (% correct) score (r = 0.68, p < 0.0001) and an insignificant relationship with USMLE Step I (3-digit) score (r = 0.22, p = 0.13). Residents with upper quartile (>or=220) USMLE Step I (3-digit) scores for our program had higher program mean OITE YIT percentile rank scores and Abos-I (% correct) scores than residents with lower quartile scores (or=55) for the program mean OITE YIT percentile rank score had higher Abos-I (% correct) scores than residents who did not. Residents who scored in the lower quartile for the third postgraduate year (PGY-3) program OITE YIT percentile rank score or for the program mean OITE YIT percentile rank score had a 5.2 and 5.8 time greater Abos-I failure risk, respectively. The program PGY-3 OITE YIT percentile rank score was the strongest Abos-I (% correct) score discriminator. Resident Abos-I (% correct), program mean OITE YIT, and program PGY-3 OITE YIT percentile rank scores were the strongest discriminators for Abos-II passage. Residents with a program mean OITE YIT percentile rank score >or=28, program PGY-3 OITE YIT percentile rank score >or=39, and USMLE Step I (3-digit) score >or=207 were more likely to pass Abos-I and II. Residents that had lower quartile USMLE Step I (3-digit) scores for our program had a 2.3 time greater Abos-I failure risk. Program residents with >or=2 below-average subjective clinical performance evaluations had lower Abos-I (% correct) scores but had similar Abos-I and II pass rates. CONCLUSION: Our program uses the USMLE Step I (3-digit) score as a preacceptance estimate of likely supplemental guided mentoring needs. Program mean OITE YIT percentile rank and PGY-3 OITE YIT percentile rank scores help identify educational deficiencies and predict eventual Abos-I and II passage. Subjective clinical performance evaluations provide important supplemental information regarding professionalism, communication, and patient care skills.

Review of oncology and hematology drug product approvals at the US Food and Drug Administration between July 2005 and December 2007.

BACKGROUND: The Office of Oncology Drug Products (OODP) in the Center for Drug Evaluation and Research at the US Food and Drug Administration began reviewing marketing applications for oncological and hematologic indications in July 2005. We conducted an overview of products that were reviewed by the OODP for marketing approval and the regulatory actions taken during July 2005 to December 2007. METHODS: We identified all applications that were reviewed by the OODP from July 1, 2005, through December 31, 2007, and reviewed the actions that OODP took. We also sought the basis for the actions taken, including the clinical trial design, endpoints used, patient accrual in the trial(s) supporting approval, and the type of regulatory approval. RESULTS: During the study period, the OODP reviewed marketing applications for 60 new indications and took regulatory action on 58 indications. Regulatory action was based on a risk-benefit evaluation of the data submitted with each application. Products that demonstrated efficacy and had an acceptable risk-benefit ratio were granted either regular or accelerated marketing approval for use in the specific indication that was studied. Regular approval was based on endpoints that demonstrated that the drug provided clinical benefit as evidenced by a longer or better life or a favorable effect on an established surrogate for a longer or better life. Accelerated approval was based on a less well-established surrogate endpoint that was reasonably likely to predict a longer or better life. Of the 53 new indications that were approved during the study period, 39 received regular approval, nine received accelerated approval, and five were converted from accelerated to regular approval. Five applications were not approved, and two applications were withdrawn before any regulatory action was taken. Eighteen of the 53 indications that were approved were for new molecular entities. CONCLUSION: During the study period, regulatory action was taken on 58 of the 60 marketing applications. Fifty-three applications were approved. A variety of clinical trial endpoints were used in the approval trials.

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.

Are preoperative health-related quality of life scores predictive of clinical outcomes after lumbar fusion?

STUDY DESIGN: Prospective longitudinal cohort. OBJECTIVE: This study evaluated the effect of preoperative Mental Component Summary (MCS), preoperative Physical Component Summary (PCS), preoperative Oswestry Disability Index (ODI), back pain predominance, body mass index (BMI), age, smoking status, and workers' compensation on health-related quality of life after lumbar fusion. These factors were selected as they are readily available and may influence a surgeon's decision-making process. SUMMARY OF BACKGROUND DATA: Measures of health-related quality of life are increasingly used to evaluate treatment effectiveness. However, their use as a predictive tool to determine which patients will improve has been limited. METHODS: The Short Form 36 (SF-36) and ODI were collected before surgery and two years after surgery in 489 patients undergoing lumbar fusion for degenerative disorders. Linear regression modeling was used to determine the effect of preoperative MCS, preoperative PCS, preoperative ODI, back pain predominance, BMI, age, smoking status, and workers' compensation on the change in ODI and change in SF-36 PCS two years after lumbar fusion. RESULTS: Patients with better preoperative MCS (P = 0.008) and worse preoperative ODI scores (P < 0.0001) achieved greater ODI improvement. Workers' compensation patients did significantly worse (P = 0.03). Patients with better preoperative MCS (P = 0.0004), better preoperative PCS (P = 0.0155), and worse preoperative ODI scores (P = 0.0210) achieved greater PCS improvement. Those on workers' compensation had lower changes in PCS, an effect that was nearly significant (P = 0.0644). There were no significant correlations between PCS and ODI improvement and back pain predominance, BMI, age, and smoking status. Attempts at determining threshold values for MCS, PCS, and ODI that are predictive of a patient achieving minimum clinically important difference for PCS and ODI were unsuccessful. CONCLUSION: Patients with good preoperative MCS and poor preoperative ODI scores who are not on workers' compensation are more likely to improve after lumbar fusion. Threshold values for MCS, PCS, and ODI predictive of a patient achieving minimum clinically important difference for PCS and ODI could not be determined.