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Among patients with a history of skin cancer, nicotinamide treatment was associated with a 23% lower rate of new nonmelanoma (basal-cell and squamous-cell) skin cancers than placebo, resulted in 13% fewer actinic keratoses after 12 months, and had similar adverse effects. Nonmelanoma skin cancers, mainly basal-cell carcinomas and squamous-cell carcinomas, are the most common cancers in white populations. 1 In Australia, nonmelanoma skin cancers are four times as common as all other cancers combined, 2 , 3 and in the United States, the annual total cost of treating nonmelanoma skin cancers is estimated to be $4.8 billion. 4 Basal-cell carcinomas rarely metastasize but are locally invasive and can be disfiguring. 5 Squamous-cell carcinomas, especially less well-differentiated tumors on the head and neck, have metastatic potential and may originate from premalignant actinic keratoses. 6 Nonmelanoma skin cancers and actinic keratoses are caused primarily by exposure to ultraviolet (UV) . . .

In a placebo-controlled trial involving immunosuppressed organ-transplant recipients, oral nicotinamide (500 mg twice daily) for 12 months did not lead to lower numbers of keratinocyte cancers or actinic keratoses.

Methylation of the promoter region of the O ( 6 ) -methylguanine-DNA methyltransferase (MGMT) gene is known to be predictive of response to temozolomide treatment in patients with glioblastoma. Contrastingly, little is known about variation in the methylation status of the MGMT promoter after treatment or across different regions of the same tumor. About 22 samples from 10 patients who had undergone multiple resections of a glioblastoma were examined with promoter sequencing. Of these, 20 were also analyzed using Methylation Specific PCR (MSP). The methylation status of the MGMT promoter was altered in the specimens obtained pre and post treatment in 2 of 9 samples as assessed by MSP and 7 out of 10 patients as assessed by promoter sequencing. In four patients, the MGMT promoter was unmethylated at primary surgery, but displayed some methylation (32, 44, 12, and 4%) on post-treatment sampling. Alteration in MSP status from unmethylated to methylated was also observed in 2 of these 4 patients. In another patient, methylation increased from 40% on initial sampling to 68% on the second sample. The remaining two patients initially demonstrated some degree of methylation (72% and 12%); subsequent sampling showed no methylation of the MGMT promoter. To ensure variable methylation status was not due to intra-tumoral variability, three to four specimens were sampled from different regions of large glioblastomas (n = 7). Promoter sequencing revealed minimal variation in methylation in all but two sites examined. Immunohistochemistry also demonstrated minimal change in MGMT expression across the tumors. This suggests that variation in MGMT promoter methylation can occur within the same tumor after treatment, necessitating caution in clinical decision-making based on this analysis.

Methylation of the promoter region of the O 6 -methylguanine-DNA methyltransferase ( MGMT ) gene is known to be predictive of response to temozolomide treatment in patients with glioblastoma. Contrastingly, little is known about variation in the methylation status of the MGMT promoter after treatment or across different regions of the same tumor. About 22 samples from 10 patients who had undergone multiple resections of a glioblastoma were examined with promoter sequencing. Of these, 20 were also analyzed using Methylation Specific PCR (MSP). The methylation status of the MGMT promoter was altered in the specimens obtained pre and post treatment in 2 of 9 samples as assessed by MSP and 7 out of 10 patients as assessed by promoter sequencing. In four patients, the MGMT promoter was unmethylated at primary surgery, but displayed some methylation (32, 44, 12, and 4%) on post-treatment sampling. Alteration in MSP status from unmethylated to methylated was also observed in 2 of these 4 patients. In another patient, methylation increased from 40% on initial sampling to 68% on the second sample. The remaining two patients initially demonstrated some degree of methylation (72% and 12%); subsequent sampling showed no methylation of the MGMT promoter. To ensure variable methylation status was not due to intra-tumoral variability, three to four specimens were sampled from different regions of large glioblastomas ( n  = 7). Promoter sequencing revealed minimal variation in methylation in all but two sites examined. Immunohistochemistry also demonstrated minimal change in MGMT expression across the tumors. This suggests that variation in MGMT promoter methylation can occur within the same tumor after treatment, necessitating caution in clinical decision-making based on this analysis.

Methylation of the promoter region of the O super(6)-methylguanine-DNA methyltransferase (MGMT) gene is known to be predictive of response to temozolomide treatment in patients with glioblastoma. Contrastingly, little is known about variation in the methylation status of the MGMT promoter after treatment or across different regions of the same tumor. About 22 samples from 10 patients who had undergone multiple resections of a glioblastoma were examined with promoter sequencing. Of these, 20 were also analyzed using Methylation Specific PCR (MSP). The methylation status of the MGMT promoter was altered in the specimens obtained pre and post treatment in 2 of 9 samples as assessed by MSP and 7 out of 10 patients as assessed by promoter sequencing. In four patients, the MGMT promoter was unmethylated at primary surgery, but displayed some methylation (32, 44, 12, and 4%) on post-treatment sampling. Alteration in MSP status from unmethylated to methylated was also observed in 2 of these 4 patients. In another patient, methylation increased from 40% on initial sampling to 68% on the second sample. The remaining two patients initially demonstrated some degree of methylation (72% and 12%); subsequent sampling showed no methylation of the MGMT promoter. To ensure variable methylation status was not due to intra-tumoral variability, three to four specimens were sampled from different regions of large glioblastomas (n = 7). Promoter sequencing revealed minimal variation in methylation in all but two sites examined. Immunohistochemistry also demonstrated minimal change in MGMT expression across the tumors. This suggests that variation in MGMT promoter methylation can occur within the same tumor after treatment, necessitating caution in clinical decision-making based on this analysis.

Western Eurasia witnessed several large-scale human migrations during the Holocene 1 – 5 . Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes—mainly from the Mesolithic and Neolithic periods—from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a ‘great divide’ genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 bp , consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 bp , resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a ‘Neolithic steppe’ cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations. An analysis involving the shotgun sequencing of more than 300 ancient genomes from Eurasia reveals a deep east–west genetic divide from the Black Sea to the Baltic, and provides insight into the distinct effects of the Neolithic transition on either side of this boundary.

AimsTo investigate trends in representation of women among authors and editorial boards of surgical pathology journals over the last two decades.Secondary aims: to identify barriers and potential solutions.MethodsThe names and gender of first, middle, last authors and editorial board members were obtained from original articles from seven pathology journals from various geopolitical regions in 2002, 2011 and 2021. The proportion of women first, middle, last authors and editorial board members were compared over time.Results1097 publications and 8012 individual authors were extracted. In 2002, 2011 and 2021, respectively, the percentage of women first authors were 28.3% (257 of 907), 31.9% (566 of 1773) and 41.1% (1421 of 3457); women middle authorship rates were 30.0% (159 of 530), 32.8% (375 of 1145) and 40.9% (1067 of 2609) and women last authors were 18.0% (34 of 188), 26.0% (82 of 315) and 36.0% (152 of 422). Women representation on editorial boards has increased (11.3%, 15.8%, 26.5%), but of the chief editors, there was only one woman in 2021, while all were men in 2002 and 2011.ConclusionsTo our knowledge, this study is the first to document under-representation of women among authors and editorial boards of surgical pathology journals. While women representation has increased over time, predominance of men remains relative to workforce proportions. Our findings are comparable to those from other medical fields and prompt the need to investigate the underlying causes for this imbalance and implement strategies to promote diversity, equity and inclusion in academic surgical pathology.

Context.-There is a global decline in medical graduates pursuing pathology careers, resulting in a broadening gap between workforce demand and supply. Objective.-To determine causes of low popularity of pathology as a career and develop strategies to avoid a workforce crisis. Design.-An online survey was distributed and yielded 1247 responses, including 609 Australian medical students from 10 medical schools, 119 prevocational doctors from 10 major teaching hospitals in New South Wales, 175 residents, and 344 pathologists throughout Australia. Results.-Compared with pathology-uninterested peers, students and prevocational doctors interested in pathology careers were more likely to value research opportunities (57 of 166 [34.3%] pathology-interested respondents versus 112 of 521 [21.5%] pathology-uninterested respondents; odds ratio [OR] = 1.91, P <.001), have children (19 of 165 respondents [11.5%] versus 22 of 522 respondents [4.2%]; OR = 2.96, P <.001), and self-identify as introverted (87 of 167 respondents [52.1%] versus 179 of 526 respondents [34%]; OR = 2.1, P <.001). Those uninterested in pathology were more likely to value patient interaction (363 of 524 respondents [69.3%] versus 71 of 166 respondents [42.8%]; OR = 3.02, P <.001). Lack of exposure to pathology was the most-cited reason for rejecting pathology (after lack of patient interaction). There was poor understanding of the role of pathologists and low confidence in the ability to interpret histopathology reports among medical students and prevocational doctors. Negative stereotypes regarding pathologists were identified. Conclusions.-Active interventions increasing exposure of medical students and prevocational doctors to pathology as a career, as well as promotion of research opportunities and potential for work-life balance, are needed to address pending workforce shortages.

The mountain cryosphere and groundwater play pivotal roles in shaping the hydrological cycle, yet their connectivity remains incompletely understood. Current knowledge on meltwater recharge and consequent groundwater discharge processes is better developed for snow–groundwater connectivity than for glacier–groundwater connectivity. Estimates of meltwater recharge vary considerably, which is probably a function of not only inherent catchment characteristics but also of the different spatio-temporal scales involved and the uncertainties in the methods used. This hinders a comprehensive understanding of the mountain water cycle. As glaciers retreat, permafrost thaws and snowpack diminishes, the relative importance of mountain groundwater is expected to increase. However, shifting and declining recharge from the cryosphere may decrease absolute groundwater amounts and fluxes with as-yet unknown effects on catchment-scale hydrological processes. We therefore stress the need to better quantify mountain cryosphere–groundwater connectivity to predict climate change impacts on mountain water supply and to support sustainable water resource management of downstream socio-ecological systems.This Perspective reviews the current understanding of groundwater recharge by meltwater, discusses the scales at which cryosphere–groundwater interactions are relevant, identifies key cryo-hydrogeological processes that need further study, and emphasizes the critical importance of these interactions for current and future water availability in mountain regions.

Scaffold-guided bone regeneration is poised to revolutionize the management of critical-sized bone defects. However, translation into clinical practice has been hampered by the focus on bioresorbable scaffolds where the rate of degradation needs to match the rate of bone formation and metal plates are required to overcome their mechanical limitations. Metal plates are problematic because they cause stress shielding and X-ray perturbation, increasing the likelihood of hardware failure and interfering with post-operative radiotherapy and imaging. Segmental defects of the mandible are challenging due to high tensile and shear stresses encountered during mastication, with the ovine mandible especially vexing because of the high repetitive loads. Here we show long-term reconstruction of ovine segmental mandibulectomy defects using a permanent, patient-matched, numerically optimized, 3D-printed, thermally toughened, plasma-treated, and laser-sintered polyetherketone gyroid scaffold housing a resorbable ceramic lattice infused with a stem cell laden hydrogel serving as an osteoinductive reservoir of calcium. The durable clinical performance observed indicates a translatable alternative to traditional reconstruction using bone grafts with metal plate fixation. Scaffold-guided bone regeneration is a promising treatment strategy for segmental defects, but clinical translation has been hindered, partially by mechanical function limitations. Here, Clark et al. describes a permanent printed polymer with a resorbable stem cell laden ceramic core for reconstructing segmental mandibular defects, which is tested in an ovine model.