arl

African skeletons from early colonial Mexico tell the story of first-generation slaves

(Max Planck Institute for the Science of Human History) Three 16th-century skeletons from a mass burial in Mexico City highlight the role of the transatlantic slave trade in introducing and disseminating new pathogens to the Americas. Researchers from the Max Planck Institute for the Science of Human History and Escuela Nacional de Antropología e Historia in Mexico analyzed skeletal features, genetic data and isotopes to explore the life history of three enslaved Africans and explore the wide-ranging impacts of massive forced migration.




arl

COVID prank nearly kills St Mary man

A practical joke gone too far caused a St Mary resident, Byron Wilson, to burst into tears after he received a phone call from one of his mischievous friends telling him that he may be a carrier of the novel coronavirus. "A dead mi dead right...




arl

Columbia-Harlem Small Business Development Center Is a Lifeline for Business Owners

The SBDC offers resources and guidance to Harlem’s small businesses amidst the COVID-19 crisis.




arl

Combined Visual and Semi-quantitative Evaluation Improves Outcome Prediction by Early Mid-treatment 18F-fluoro-deoxi-glucose Positron Emission Tomography in Diffuse Large B-cell Lymphoma.

The purpose of this study was to assess the predictive and prognostic value of interim FDG PET (iPET) in evaluating early response to immuno-chemotherapy after two cycles (PET-2) in diffuse large B-cell lymphoma (DLBCL) by applying two different methods of interpretation: the Deauville visual five-point scale (5-PS) and a change in standardised uptake value by semi-quantitative evaluation. Methods: 145 patients with newly diagnosed DLBCL underwent pre-treatment PET (PET-0) and PET-2 assessment. PET-2 was classified according to both the visual 5-PS and percentage SUV changes (SUV). Receiver operating characteristic (ROC) analysis was performed to compare the accuracy of the two methods for predicting progression-free survival (PFS). Survival estimates, based on each method separately and combined, were calculated for iPET-positive (iPET+) and iPET-negative (iPET–) groups and compared. Results: Both with visual and SUV-based evaluations significant differences were found between the PFS of iPET– and iPET+ patient groups (p<0.001). Visually the best negative (NPV) and positive predictive value (PPV) occurred when iPET was defined as positive if Deauville score 4-5 (89% and 59%, respectively). Using the 66% SUV cut-off value, reported previously, NPV and PPV were 80 and 76%, respectively. SUV at 48.9% cut-off point, reported for the first time here, produced 100% specificity along with the highest sensitivity (24%). Visual and semi-quantitative SUV<48.9% assessment of each PET-2 gave the same PET-2 classification (positive or negative) in 70% (102/145) of all patients. This combined classification delivered NPV and PPV of 89% and 100% respectively, and all iPET+ patients failed to achieve or remain in remission. Conclusion: In this large consistently treated and assessed series of DLBCL, iPET had good prognostic value interpreted either visually or semi-quantitatively. We determined that the most effective SUV cut-off was at 48.9%, and that when combined with visual 5-PS assessment, a positive PET-2 was highly predictive of treatment failure.




arl

Pre-treatment 18F-FDG PET/CT Radiomics predict local recurrence in patients treated with stereotactic radiotherapy for early-stage non-small cell lung cancer: a multicentric study

Purpose: The aim of this retrospective multicentric study was to develop and evaluate a prognostic FDG PET/CT radiomics signature in early-stage non-small cell lung cancer (NSCLC) patients treated with stereotactic radiotherapy (SBRT). Material and Methods: Patients from 3 different centers (n = 27, 29 and 8) were pooled to constitute the training set, whereas the patients from a fourth center (n = 23) were used as the testing set. The primary endpoint was local control (LC). The primary tumour was semi-automatically delineated in the PET images using the Fuzzy locally adaptive Bayesian algorithm, and manually in the low-dose CT images. A total of 184 IBSI-compliant radiomic features were extracted. Seven clinical and treatment parameters were included. We used ComBat to harmonize radiomic features extracted from the four institutions relying on different PET/CT scanners. In the training set, variables found significant in the univariate analysis were fed into a multivariate regression model and models were built by combining independent prognostic factors. Results: Median follow-up was 21.1 (1.7 – 63.4) and 25.5 (7.7 – 57.8) months in training and testing sets respectively. In univariate analysis, none of the clinical variables, 2 PET and 2 CT features were significantly predictive of LC. The best predictive models in the training set were obtained by combining one feature from PET, namely information correlation 2 (IC2) and one from CT (Flatness), reaching a sensitivity of 100% and a specificity of 96%. Another model combining 2 PET features (IC2 and Strength), reached sensitivity of 100% and specificity of 88%, both with an undefined hazard ratio (HR) (p<0.001). The latter model obtained an accuracy of 0.91 (sensitivity 100%, specificity 81%), with a HR undefined (P = 0.023) in the testing set, however other models relying on CT radiomics features only or the combination of PET and CT features failed to validate in the testing set. Conclusion: We showed that two radiomic features derived from FDG PET were independently associated with LC in patients with NSCLC undergoing SBRT and could be combined in an accurate predictive model. This model could provide local relapse-related information and could be helpful in clinical decision-making.




arl

Label-free Visualization of Early Cancer Hepatic Micrometastasis and Intraoperative Image-guided Surgery by Photoacoustic Imaging

Objectives: The detection of cancer micrometastasis for early diagnosis and treatment poses a great challenge for conventional imaging techniques. The aim of study is to evaluate the performance of photoacoustic imaging (PAI) in detecting hepatic micrometastases from melanoma in a very early stage and perform tumor resection by intraoperative photoacoustic image-guidance. Methods: In vivo studies were performed by following protocols approved by the Ethical Committee for Animal Research at Xiamen University. First, a B16 melanoma hepatic metastasis mouse model (n = 10) was established to study the development of micrometastases in vivo. Next, the hepatic metastasis mice models were imaged by scalable PAI instrument, ultrasound, 9.4 T high-resolution magnetic resonance imaging (MRI), positron emission tomography/computed tomography (PET/CT), and bioluminescence imaging. Photoacoustic images acquired with optical wavelengths spanning from 680 to 850 nm were spectrally unmixed by using a linear least-squares method to differentiate various components. Differences in the signal-to-background ratios among different modalities were determined with the two-tailed paired t test. The diagnosis results were assessed with histologic examinations. Excised liver samples from patients diagnosed with hepatic cancer were also examined to identify tumor boundary. In vivo metastatic melanoma removal in surgery was precisely guided by the portable PAI system. Results: PAI achieved as small as ~400 µm hepatic melanoma detection at a depth up to 7 mm in vivo, which could early detect small melanoma compared with ultrasound and MRI in mouse models. The signal ratio of tumor-to-liver acquired with PAI in micrometastases at 8 days (4.2 ± 0.2, n = 6) and 14 days (9.2 ± 0.4, n = 5) were significantly higher than those obtained with PET/CT (1.8 ± 0.1, n = 5 and 4.5 ± 0.2, n = 5, P <0.001 for both). Functional PAI provided dynamic oxygen saturation changes during tumor growth. The limit of detection was measured to be approximately 219 cells per microliter in vitro. We successfully performed intraoperative photoacoustic image-guided surgery in vivo using the rapid portable PAI system. Conclusion: Our findings offer a rapid and effective tool to noninvasively detect micrometastases and guide intraoperative resection as a complementary clinical imaging application.




arl

Early Detection in a Mouse Model of Pancreatic Cancer by Imaging DNA Damage Response Signalling

Rationale: Despite its widespread use in oncology, the PET radiotracer 18F-FDG is ineffective for improving early detection of pancreatic ductal adenocarcinoma (PDAC). An alternative strategy for early detection of pancreatic cancer involves visualisation of high-grade pancreatic intraepithelial neoplasias (PanIN-3), generally regarded as the non-invasive precursors of PDAC. The DNA damage response is known to be hyper-activated in late-stage PanINs. Therefore, we investigated whether the SPECT imaging agent, 111In-anti-H2AX-TAT, allows visualisation of the DNA damage repair marker H2AX in PanIN-3s in an engineered mouse model of PDAC, to facilitate early detection of PDAC. Methods: Genetically engineered KPC mice (KRasLSL.G12D/+; p53LSL.R172H/+; PdxCre) were imaged with 18F-FDG and 111In-anti-H2AX-TAT. PanIN/PDAC presence visualised by histology was compared with autoradiography and immunofluorescence. Separately, the survival of KPC mice imaged with 111In-anti-H2AX-TAT was evaluated. Results: In KPC mouse pancreata, H2AX expression was increased in high-grade PanINs, but not in PDAC, corroborating earlier results obtained from human pancreas sections. Uptake of 111In-anti-H2AX-TAT, but not 111In-IgG-TAT or 18F-FDG, within the pancreas was positively correlated with the age of KPC mice, which was correlated with the number of high-grade PanINs. 111In-anti-H2AX-TAT localises preferentially in high-grade PanIN lesions, but not in established PDAC. Younger, non-tumour-bearing KPC mice that show uptake of 111In-anti-H2AX-TAT in the pancreas survive significantly shorter than mice with physiological 111In-anti-H2AX-TAT uptake. Conclusion: 111In-anti-H2AX-TAT imaging allows non-invasive detection of DNA damage repair signalling upregulation in pre-invasive PanIN lesions and is a promising new tool to aid in the early detection and staging of pancreatic cancer.




arl

Multi-phasic 68Ga-PSMA PET/CT in detection of early recurrence in prostate cancer patients with PSA < 1 ng/ml: a prospective study of 135 cases.

Purpose: The main objective of this prospective study was to determine the impact of multi-phasic acquisition of 68Ga-PSMA PET/CT in the detection of recurrent prostate cancer (PCa) in the early stage of biochemical recurrence (BR) with prostate-serum-antigen (PSA) level <1ng/ml. Also, 68Ga-PSMA PET/CT positivity was correlated with clinical parameters for the assessment of predictive markers. Methods: A prospective monocentric study was conducted on 135 PCa patients with BR and PSA<1ng/ml. All patients have undergone initial prostatectomy with additional radiation therapy in 19.3% and androgen-deprivation therapy (ADT) in 7.4% of patients. Dynamic acquisition [1–8min. post-injection (p.i.)] from the prostate bed, standard whole-body (60min. p.i.) and limited bed positions of delayed studies (120-150min. p.i.), were performed. Studies were reviewed by two board-certified nuclear medicine specialists, independently. A combination of visual and semi-quantitative analyses and correlation with morphological (e.g. MRI) and/or clinical follow-up findings was used for the final interpretation of abnormal lesions as benign or malignant. 68Ga-PSMA PET/CT positivity was also correlated with primary clinical findings. Results: Incorporating the information of all phases, 116 lesions were detected in 49.6% of patients (22 local recurrences, 63 lymph nodes, and 31 distant metastases). The detection rates were 31.8%, 44.9%, and 71.4% for PSA<0.2ng/ml, 0.2≤PSA<0.5, and 0.5≤PSA<1, respectively. Additional dynamic and/or delayed phases resulted in better determination of equivocal lesions and a higher diagnostic performance in 25.9% of patients. Stand-alone dynamic and delayed images led to better interpretation of equivocal findings in the prostate bed (31.4%) and other (lymph node/bone) lesions (20%), respectively. Conclusion: 68Ga-PSMA PET/CT revealed promising results for the early detection of recurrent disease in patients with PSA level of 0.5-1.0ng/ml. However, it showed limited value in cases with PSA<0.5ng/ml. Multi-phasic 68Ga-PSMA PET/CT led to better determination of equivocal findings. Although, dynamic images may provide helpful information in assessment of the prostate bed; however, delayed acquisitions seem to have higher impact in clarifying of the equivocal findings.




arl

Early prostate-specific antigen changes and clinical outcome following 177Lu-PSMA radionuclide treatment in patients with metastatic castration-resistant prostate cancer

Background: Prostate-specific antigen (PSA) is widely used to monitor treatment response in patients with metastatic castration-resistant prostate cancer (mCRPC). However, PSA measurements are considered only after 12 wk of treatment. We aimed to evaluate the prognostic value of early PSA changes following 177Lu-labelled prostate specific membrane antigen (LuPSMA) radionuclide treatment in mCRPC patients. Methods: Men who were treated under a compassionate access program with LuPSMA at our institution and had available PSA values at baseline, at 6 wk after treatment initiation were included in this retrospective analysis. Patients were assigned to three groups based on PSA changes: 1) response: ≥30% decline, 2) progression: ≥25% increase and 3) stable: <30% decline and <25% increase. The co-primary endpoints were overall survival and imaging-based progression-free survival. The secondary end points were PSA changes at 12 wk and PSA flare-up. Results: We identified 124 eligible patients with PSA values at 6 wk. A ≥30% decline in PSA at 6 wk was associated with longer overall survival (median 16.7 mo; 95%CI 14.4–19.0) compared with patients with stable PSA (median: 11.8 mo; 95%CI 8.6–15.1; P = 0.007) and progression (median: 6.5 mo; 95%CI 5.2–7.8; p<0.001). Patients with ≥30% decline in PSA at 6 wk also had a reduced risk of imaging-based progression compared with patients with stable PSA (HR: 0.60; 95%CI 0.38–0.94; P = 0.02), while patients with PSA progression had a higher risk of imaging-based progression compared with those showing stable PSA (HR: 3.18; 95%CI 1.95–5.21; p<0.001). The percentage changes of PSA at 6 wk and 12 wk were highly associated (r=0.90; p<0.001). 29 of 31 (94%) patients who experienced early PSA progression at 6 wk achieved biochemical progression at 12 wk. Overall, only 1 of 36 (3%) patients with PSA progression at 6 wk achieved any PSA decline at 12 wk (1% of the entire cohort). Limitations of the study included its retrospective nature and the single center experience. Conclusion: PSA changes at 6 wk after LuPSMA initiation are an early indicator of long-term clinical outcome. Patients progressing by PSA after 6 wk of treatment could benefit from a very early treatment switch decision. PSA flare-up during LuPSMA treatment is very uncommon. Prospective studies are now warranted to validate our findings and potentially inform clinicians earlier on the effectiveness of LuPSMA.




arl

Peptidomic Analysis of Urine from Youths with Early Type 1 Diabetes Reveals Novel Bioactivity of Uromodulin Peptides In Vitro [Research]

Chronic hyperglycemia is known to disrupt the proteolytic milieu, initiating compensatory and maladaptive pathways in the diabetic kidney. Such changes in intrarenal proteolysis are captured by the urinary peptidome. To elucidate the early kidney response to chronic hyperglycemia, we conducted a peptidomic investigation into urines from otherwise healthy youths with type 1 diabetes and their non-diabetic peers using unbiased and targeted mass spectrometry-based techniques. This cross-sectional study included two separate cohorts for the discovery (n = 30) and internal validation (n = 30) of differential peptide excretion. Peptide bioactivity was predicted using PeptideRanker and subsequently verified in vitro. Proteasix and the Nephroseq database were used to identify putative proteases responsible for peptide generation and examine their expression in diabetic nephropathy. A total of 6550 urinary peptides were identified in the discovery analysis. We further examined the subset of 162 peptides, which were quantified across all thirty samples. Of the 15 differentially excreted peptides (p < 0.05), seven derived from a C-terminal region (589SGSVIDQSRVLNLGPITRK607) of uromodulin, a kidney-specific protein. Increased excretion of five uromodulin peptides was replicated in the validation cohort using parallel reaction monitoring (p < 0.05). One of the validated peptides (SGSVIDQSRVLNLGPI) activated NFB and AP-1 signaling, stimulated cytokine release, and enhanced neutrophil migration in vitro. In silico analyses highlighted several potential proteases such as hepsin, meprin A, and cathepsin B to be responsible for generating these peptides. In summary, we identified a urinary signature of uromodulin peptides associated with early type 1 diabetes before clinical manifestations of kidney disease and discovered novel bioactivity of uromodulin peptides in vitro. Our present findings lay the groundwork for future studies to validate peptide excretion in larger and broader populations, to investigate the role of bioactive uromodulin peptides in high glucose conditions, and to examine proteases that cleave uromodulin.




arl

Integration of IgA and IgG Autoantigens Improves Performance of Biomarker Panels for Early Diagnosis of Lung Cancer [Research]

Lung cancer (LC) remains the leading cause of mortality from malignant tumors worldwide. In our previous study, we surveyed both IgG and IgM-bound serological biomarkers and validated a panel of IgG-bound autoantigens for early LC diagnosis with 50% sensitivity at 90% specificity. To further improve the performance of these serological biomarkers, we surveyed HuProt arrays, comprised of 20,240 human proteins, for IgA-bound autoantigens because IgAs are a major immunoglobulin isotype in the lung. Integrating with IgG-bound autoantigens, we discovered and validated a combined biomarker panel using ELISA-format tests. Specifically, in Phase I, we obtained IgA-based autoimmune profiles of 69 early stage LC patients, 30 healthy subjects and 25 patients with lung benign lesions (LBL) on HuProt arrays and identified 28 proteins as candidate autoantigens that were significantly associated with early stage LC. In Phase II, we re-purified the autoantigens and converted them into an ELISA-format testing to profile an additional large cohort, comprised of 136 early stage LC patients, 58 healthy individuals, and 29 LBL patients. Integration of IgG autoimmune profiles allowed us to identify and validate a biomarker panel of three IgA autoantigens (i.e. BCL7A, and TRIM33 and MTERF4) and three IgG autoantigens (i.e. CTAG1A, DDX4 and MAGEC2) for diagnosis of early stage LC with 73.5% sensitivity at >85% specificity. In Phase III, the performance of this biomarker panel was confirmed with an independent cohort, comprised of 88 early stage LC patients, 18 LBL patients, and 36 healthy subjects. Finally, a blind test on 178 serum samples was conducted to confirm the performance of the biomarker panel. In summary, this study demonstrates for the first time that an integrated panel of IgA/IgG autoantigens can serve as valuable biomarkers to further improve the performance of early diagnosis of LC.




arl

Three Takeaways From the Belarusian Parliamentary Elections

28 November 2019

Ryhor Astapenia

Robert Bosch Stiftung Academy Fellow, Russia and Eurasia Programme
Lukashenka’s domestic support is waning and he is not willing to make concessions to the West. Instead, he is trying to appease the ruling cadre.

2019-11-28-Luk.jpg

Alexander Lukashenka leaves a voting booth on 17 November. Photo: Getty Images.

Belarus’s parliamentary elections, held on 17 November, were predictably non-transparent, with numerous violations. The regime of Alexander Lukasheka allowed no opposition candidates as members of parliament – in contrast to the previous parliament, in which there were two opposition MPs. While this might seem to be a return to ‘business as usual’, three key takeaways from the elections highlight a shifting political and social landscape.

1. Lukashenka is appeasing his ruling cadre by promising to increase their role in the political system.

With several influential officials becoming new MPs, it is more likely that parliament will be more involved in any forthcoming discussion of a new constitution. Lukashenka has been promising constitutional reform for several years; he has said publicly that it will lead to an increased significance of government agencies as well as parliament. The aim of this is to keep them more engaged and on Lukashenka’s side.

In terms of the composition of the new parliament itself, there are some key differences with previous years. It is no longer a comfortable place for officials to while away their pre-retirement: many MPs are now in their fifties or younger, and have plans for careers beyond parliament.

It also looks as if small steps are being taken towards the emergence of a party system in Belarus. The leader of Belaya Rus, a pro-government association of Belarusian officials, got a seat in parliament for the first time, increasing the likelihood of it becoming a political party. The number of MPs from different parties has increased to 21 (out of 110 in total). Although these still all broadly support Lukashenka, they can differ from the president in policy positions. For example, the Labour and Justice Party, with 6 seats in parliament, supported the annexation of Crimea in 2014. Change, of course, may not necessarily be in a pro-Western direction.

Moreover, the newly elected members of parliament look more like real politicians. They go to debates, speak to independent journalists and have their own social media channels. Some have even felt able to criticize the actions of the authorities.

Similar changes have been taking place in other institutions in Belarus. The government is now more competent than it has ever been. The National Bank has managed to carry out macroeconomic stabilization on one of the most unstable currencies in Europe, while the ministries responsible for the economic development have implemented certain small-scale reforms. The Minister of the Interior has even acknowledged mistakes made by his department (under his predecessor), and undertaken to make improvements.

This has resulted in a near-comical situation, whereby the Belarusian non-state media outlets have an increasingly positive view of some state officials, such as Prime Minister Siarhei Rumas, while the state media has been scaling back its coverage of him to ensure he does not become too popular.

2. Belarus has less need for the West and is reluctant to make even small concessions.

Since the slight warming of Belarusian relations with the West in 2014, Lukashenka has been having more meetings with prominent Western officials. Western institutions began trying to cooperate more closely with Belarus, but soon saw that it was not very interested. In 2018, the European Bank of Reconstruction and Development allocated €360 million to Belarus. However, it is now considering a reduction, as reforms in Belarus have not, in its view, gone far enough. The European Union has also committed considerable time and money to regional authorities, but this has not brought any significant changes to Belarusian local government.

The absence of opposition candidates also demonstrates that the Belarusian authorities are prepared for a new deterioration of relations with the West. The authorities could certainly have afforded some opposition in parliament, especially since they themselves choose whom to appoint. Given that they did not, they either do not consider worsened relations a problem or are confident that the West will continue to cooperate with Belarus in order to limit Russian power, regardless of its violations of the rule of law.

3. There is growing popular dissatisfaction with the current regime, but the state has no good plan for how to deal with it.

Parliamentary election campaigns in Belarus are traditionally low-key, but this year they were particularly muted. The authorities tried to ensure that people knew as little about the election as possible. Campaign posters appeared on the streets just two weeks before polling day. It seems the authorities were reluctant to politicize society, as further resentment at autocratic rule is brewing.

Many Belarusians who previously supported Lukashenka now have a very critical opinion of him. Take political blogging: the most popular political blogger in Belarus is a 22-year-old man who goes by the name of NEXTA. He produces low-quality videos which are highly critical of the authorities. A film by him about Lukashenka, released a month ago, has already received 1.8 million views, even though there are only 9.5 million people in Belarus.

The authorities are not in a concessionary mood. The presidential elections in 2020 will also likely be a sham. If the authorities’ grip over the country is weakened, they will fear an outbreak of anger, resulting in widespread protests which the regime might once again have to meet with violence.




arl

Dopamine and Early Retinal Dysfunction in Diabetes: Insights From a Phase 1 Study




arl

Three Takeaways From the Belarusian Parliamentary Elections

28 November 2019

Ryhor Astapenia

Robert Bosch Stiftung Academy Fellow, Russia and Eurasia Programme
Lukashenka’s domestic support is waning and he is not willing to make concessions to the West. Instead, he is trying to appease the ruling cadre.

2019-11-28-Luk.jpg

Alexander Lukashenka leaves a voting booth on 17 November. Photo: Getty Images.

Belarus’s parliamentary elections, held on 17 November, were predictably non-transparent, with numerous violations. The regime of Alexander Lukasheka allowed no opposition candidates as members of parliament – in contrast to the previous parliament, in which there were two opposition MPs. While this might seem to be a return to ‘business as usual’, three key takeaways from the elections highlight a shifting political and social landscape.

1. Lukashenka is appeasing his ruling cadre by promising to increase their role in the political system.

With several influential officials becoming new MPs, it is more likely that parliament will be more involved in any forthcoming discussion of a new constitution. Lukashenka has been promising constitutional reform for several years; he has said publicly that it will lead to an increased significance of government agencies as well as parliament. The aim of this is to keep them more engaged and on Lukashenka’s side.

In terms of the composition of the new parliament itself, there are some key differences with previous years. It is no longer a comfortable place for officials to while away their pre-retirement: many MPs are now in their fifties or younger, and have plans for careers beyond parliament.

It also looks as if small steps are being taken towards the emergence of a party system in Belarus. The leader of Belaya Rus, a pro-government association of Belarusian officials, got a seat in parliament for the first time, increasing the likelihood of it becoming a political party. The number of MPs from different parties has increased to 21 (out of 110 in total). Although these still all broadly support Lukashenka, they can differ from the president in policy positions. For example, the Labour and Justice Party, with 6 seats in parliament, supported the annexation of Crimea in 2014. Change, of course, may not necessarily be in a pro-Western direction.

Moreover, the newly elected members of parliament look more like real politicians. They go to debates, speak to independent journalists and have their own social media channels. Some have even felt able to criticize the actions of the authorities.

Similar changes have been taking place in other institutions in Belarus. The government is now more competent than it has ever been. The National Bank has managed to carry out macroeconomic stabilization on one of the most unstable currencies in Europe, while the ministries responsible for the economic development have implemented certain small-scale reforms. The Minister of the Interior has even acknowledged mistakes made by his department (under his predecessor), and undertaken to make improvements.

This has resulted in a near-comical situation, whereby the Belarusian non-state media outlets have an increasingly positive view of some state officials, such as Prime Minister Siarhei Rumas, while the state media has been scaling back its coverage of him to ensure he does not become too popular.

2. Belarus has less need for the West and is reluctant to make even small concessions.

Since the slight warming of Belarusian relations with the West in 2014, Lukashenka has been having more meetings with prominent Western officials. Western institutions began trying to cooperate more closely with Belarus, but soon saw that it was not very interested. In 2018, the European Bank of Reconstruction and Development allocated €360 million to Belarus. However, it is now considering a reduction, as reforms in Belarus have not, in its view, gone far enough. The European Union has also committed considerable time and money to regional authorities, but this has not brought any significant changes to Belarusian local government.

The absence of opposition candidates also demonstrates that the Belarusian authorities are prepared for a new deterioration of relations with the West. The authorities could certainly have afforded some opposition in parliament, especially since they themselves choose whom to appoint. Given that they did not, they either do not consider worsened relations a problem or are confident that the West will continue to cooperate with Belarus in order to limit Russian power, regardless of its violations of the rule of law.

3. There is growing popular dissatisfaction with the current regime, but the state has no good plan for how to deal with it.

Parliamentary election campaigns in Belarus are traditionally low-key, but this year they were particularly muted. The authorities tried to ensure that people knew as little about the election as possible. Campaign posters appeared on the streets just two weeks before polling day. It seems the authorities were reluctant to politicize society, as further resentment at autocratic rule is brewing.

Many Belarusians who previously supported Lukashenka now have a very critical opinion of him. Take political blogging: the most popular political blogger in Belarus is a 22-year-old man who goes by the name of NEXTA. He produces low-quality videos which are highly critical of the authorities. A film by him about Lukashenka, released a month ago, has already received 1.8 million views, even though there are only 9.5 million people in Belarus.

The authorities are not in a concessionary mood. The presidential elections in 2020 will also likely be a sham. If the authorities’ grip over the country is weakened, they will fear an outbreak of anger, resulting in widespread protests which the regime might once again have to meet with violence.




arl

Braves unwilling to meet Marlins' ask for J.T.

The Braves made it clear that, individually, each of their prospects was available in exchange for J.T. Realmuto. But they were not willing to provide the volume of prospects or the MLB-experienced asset sought by the Marlins, who ended an offseason-long saga by dealing the All-Star catcher to the Phillies on Thursday.




arl

South Africa parliament video call hacked with pornography

JOHANNESBURG (AP) — A virtual meeting of South African lawmakers has been disrupted by hackers who flooded the video call with pornographic images. In the incident on Thursday, the hackers also hurled racial and sexual insults at the meeting...




arl

Early detection of eating disorders

Assessing young people with possible eating disorders can be complex for a variety of reasons. Building a therapeutic relationship with a young person with a possible eating disorder and their family is key to enabling a thorough assessment and ongoing management, but it introduces difficult issues regarding confidentiality and risk. In this...




arl

Behind the campaign promises - Doctors in parliament

The UK general election is happening this week, and you’ve probably made your mind up which MP you’re voting for already - and maybe the NHS has influenced that decision. This year has seen an increase in the number of doctors running for parliament, and in this podcast we find out what motivates doctors to step away from clinical practice, and...




arl

De Novo Mutations in EIF2B1 Affecting eIF2 Signaling Cause Neonatal/Early-Onset Diabetes and Transient Hepatic Dysfunction

Permanent neonatal diabetes mellitus (PNDM) is caused by reduced β-cell number or impaired β-cell function. Understanding of the genetic basis of this disorder highlights fundamental β-cell mechanisms. We performed trio genome sequencing for 44 patients with PNDM and their unaffected parents to identify causative de novo variants. Replication studies were performed in 188 patients diagnosed with diabetes before 2 years of age without a genetic diagnosis. EIF2B1 (encoding the eIF2B complex α subunit) was the only gene with novel de novo variants (all missense) in at least three patients. Replication studies identified two further patients with de novo EIF2B1 variants. In addition to having diabetes, four of five patients had hepatitis-like episodes in childhood. The EIF2B1 de novo mutations were found to map to the same protein surface. We propose that these variants render the eIF2B complex insensitive to eIF2 phosphorylation, which occurs under stress conditions and triggers expression of stress response genes. Failure of eIF2B to sense eIF2 phosphorylation likely leads to unregulated unfolded protein response and cell death. Our results establish de novo EIF2B1 mutations as a novel cause of permanent diabetes and liver dysfunction. These findings confirm the importance of cell stress regulation for β-cells and highlight EIF2B1’s fundamental role within this pathway.




arl

Use of genetic variation to separate the effects of early and later life adiposity on disease risk: mendelian randomisation study




arl

Charlotte Watts

Programme Coordinator, Energy, Environment and Resources Programme

Biography

Charlotte joined Chatham House as a programme co-ordinator in the Energy, Environment and Resources (EER) department, contributing to the successful delivery of several projects including the annual Waddesdon club, the IUU fishing forum and the AFRICAP programme.

Prior to joining Chatham House, she worked in project management for an international development consultancy, managing the delivery of the UK government’s Prosperity Fund projects. 

Before this, she programme managed large scale youth programmes across 3 regions for a UK-based charity; delivering and building relationships with top executives at multinational companies. Her voluntary experience has taken her to Nicaragua, where worked on a DFID funded WASH project, assisting fellow Nicaraguan volunteers.

Charlotte has a BA (Hons) in Geography from the University of Sussex, and has completed an MSc in Population and International Development, where she focused particularly on the relationship between people and the environment, specialising in disaster risk reduction, sustainable livelihoods and climate resilience.

Areas of expertise

  • Climate resilience
  • Population growth and environmental pressures
  • Disaster risk reduction (DRR)
  • Social and cultural geographies

Past experience

2018-19Consultant, Project Manager and Prosperity Fund Coordinator, IMC Worldwide
2017-18MSc in Population and International Development, London School of Economics and Political Science (LSE)
2016-17Programme Associate Manager, The Challenge
2011-14Ba (Hons) in Geography with a focus on international development, University of Sussex




arl

Remain in Mexico Plan Echoes Earlier U.S. Policy to Deter Haitian Migration

Remain in Mexico—the Trump administration policy aimed at deterring the rising numbers of migrants from Central America by requiring them to stay in Mexico through most of their U.S. asylum adjudication process—bears striking similarities to U.S. policy in the 1980s and 1990s that sought to discourage Haitians from making the sea journey to the United States. This article explores the parallels and differences between Remain in Mexico and the earlier narrowing of asylum for Haitians.




arl

Nearly 20,000 Teens in Georgia Receive Licenses Without a Road Test

Source:

The sweaty palms on the steering wheel. The repeated exclamations of "Sorry!" The nervous glances from the examiner. They're all part of the dreaded road test, which, for decades, has been a rite of passage for every U.S. teenager to obtain a driver's license. Yet now, due to the coronavirus pandemic, nearly 20,000 teens in Georgia have received licenses without taking an official road test, and Wisconsin will soon follow suit.






arl

Starting Earlier on Lifelong Learning

By: Matt Stamps, Yale-NUS College When Yale-NUS College reviewed the curriculum for its Mathematical, Computational, and Statistical (MCS) Sciences major in the autumn of 2018, I spent several weeks reading about mathematics programs at similar institutions.  A common learning objective … Continue reading




arl

Distinct Growth Phases in Early Life Associated With the Risk of Type 1 Diabetes: The TEDDY Study

OBJECTIVE

This study investigates two-phase growth patterns in early life and their association with development of islet autoimmunity (IA) and type 1 diabetes (T1D).

RESEARCH DESIGN AND METHODS

The Environmental Determinants of Diabetes in the Young (TEDDY) study followed 7,522 genetically high-risk children in Sweden, Finland, Germany, and the U.S. from birth for a median of 9.0 years (interquartile range 5.7–10.6) with available growth data. Of these, 761 (10.1%) children developed IA and 290 (3.9%) children were diagnosed with T1D. Bayesian two-phase piecewise linear mixed models with a random change point were used to estimate children’s individual growth trajectories. Cox proportional hazards models were used to assess the effects of associated growth parameters on the risks of IA and progression to T1D.

RESULTS

A higher rate of weight gain in infancy was associated with increased IA risk (hazard ratio [HR] 1.09 [95% CI 1.02, 1.17] per 1 kg/year). A height growth pattern with a lower rate in infancy (HR 0.79 [95% CI 0.70, 0.90] per 1 cm/year), higher rate in early childhood (HR 1.48 [95% CI 1.22, 1.79] per 1 cm/year), and younger age at the phase transition (HR 0.76 [95% CI 0.58, 0.99] per 1 month) was associated with increased risk of progression from IA to T1D. A higher rate of weight gain in early childhood was associated with increased risk of progression from IA to T1D (HR 2.57 [95% CI 1.34, 4.91] per 1 kg/year) in children with first-appearing GAD autoantibody only.

CONCLUSIONS

Growth patterns in early life better clarify how specific growth phases are associated with the development of T1D.




arl

Man wins nearly $800,000 from lottery ticket bought by mistake

An Australian man who scored a lottery jackpot of nearly $800,000 said he bought his ticket by mistake while attempting to play a different drawing.




arl

Iowa man receives postcard mailed 33 years earlier

An Iowa man who received a postcard from his sister said he was surprised to note the card had been mailed in 1987.




arl

Loss of Incretin Effect Is a Specific, Important, and Early Characteristic of Type 2 Diabetes

Jens J. Holst
May 1, 2011; 34:S251-S257
Diabetes Treatments




arl

Early Signs of Cardiovascular Disease in Youth With Obesity and Type 2 Diabetes

Neslihan Gungor
May 1, 2005; 28:1219-1221
BR Pathophysiology/Complications




arl

HbA1c Levels Are Significantly Lower in Early and Late Pregnancy

Lene R. Nielsen
May 1, 2004; 27:1200-1201
Brief Reports




arl

HbA1c Levels Are Significantly Lower in Early and Late Pregnancy

Lene R. Nielsen
May 1, 2004; 27:1200-1201
Brief Reports




arl

Oil nearly flat in pause after previous session's gains

Oil prices were near flat early Thursday in what was seen as a pause after gains in the two previous sessions, as traders considered geopolitical developments.




arl

Crude oil prices rise early Friday amid supply concerns

Oil prices rose early Friday amid supply concerns following reports of smaller-than-expected stocks, and amid reduced expectation of interest rate hikes.




arl

CDC: Nearly 5,000 workers at meat processing plants diagnosed with COVID-19

Nearly 5,000 workers in 115 meat processing workers across 19 states have been diagnosed with COVID-19, according to figures released Friday by the U.S. Centers for Disease Control and Prevention.




arl

Sleep Duration Patterns in Early to Middle Adulthood and Subsequent Risk of Type 2 Diabetes in Women

OBJECTIVE

To identify sleep duration trajectories from early to middle adulthood and their associations with incident type 2 diabetes.

RESEARCH DESIGN AND METHODS

Using a group-based modeling approach, we identified sleep duration trajectories based on sleep duration in ages 20–25, 26–35, 36–45, and 46+ years, which were retrospectively assessed in 2009 among 60,068 women from the Nurses’ Health Study II (median age 54.9 years) who were free of diabetes, cardiovascular disease, and cancer. We investigated the prospective associations between sleep duration trajectories and diabetes risk (2009–2017) using multivariable Cox proportional hazards models.

RESULTS

We documented 1,797 incident diabetes cases over a median follow-up of 7.8 years (442,437 person-years). Six sleep duration trajectories were identified: persistent 5-, 6-, 7-, or 8-h sleep duration and increased or decreased sleep duration. After multivariable adjustment for diabetes risk factors, compared with the persistent 7-h sleep duration group, the hazard ratio was 1.43 (95% CI 1.10, 1.84) for the 5-h group, 1.17 (1.04, 1.33) for the 6-h group, 0.96 (0.84, 1.10) for the 8-h group, 1.33 (1.09, 1.61) for the increased sleep duration group, and 1.32 (1.10, 1.59) for the decreased sleep duration group. Additional adjustment for time-updated comorbidities and BMI attenuated these associations, although a significantly higher risk remained in the decreased sleep duration group (1.24 [1.03, 1.50]).

CONCLUSIONS

Persistent short sleep duration or changes in sleep duration from early to middle adulthood were associated with higher risk of type 2 diabetes in later life. These associations were weaker after obesity and metabolic comorbidities were accounted for.




arl

Metabolic Factors, Lifestyle Habits, and Possible Polyneuropathy in Early Type 2 Diabetes: A Nationwide Study of 5,249 Patients in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) Cohort

OBJECTIVE

To investigate the association of metabolic and lifestyle factors with possible diabetic polyneuropathy (DPN) and neuropathic pain in patients with early type 2 diabetes.

RESEARCH DESIGN AND METHODS

We thoroughly characterized 6,726 patients with recently diagnosed diabetes. After a median of 2.8 years, we sent a detailed questionnaire on neuropathy, including the Michigan Neuropathy Screening Instrument questionnaire (MNSIq), to identify possible DPN (score ≥4) and the Douleur Neuropathique en 4 Questions (DN4) questionnaire for possible associated neuropathic pain (MNSIq ≥4 + pain in both feet + DN4 score ≥3).

RESULTS

Among 5,249 patients with data on both DPN and pain, 17.9% (n = 938) had possible DPN, including 7.4% (n = 386) with possible neuropathic pain. In regression analyses, central obesity (waist circumference, waist-to-hip ratio, and waist-to-height ratio) was markedly associated with DPN. Other important metabolic factors associated with DPN included hypertriglyceridemia ≥1.7 mmol/L, adjusted prevalence ratio (aPR) 1.36 (95% CI 1.17; 1.59); decreased HDL cholesterol <1.0/1.2 mmol/L (male/female), aPR 1.35 (95% CI 1.12; 1.62); hs-CRP ≥3.0 mg/L, aPR 1.66 (95% CI 1.42; 1.94); C-peptide ≥1,550 pmol/L, aPR 1.72 (95% CI 1.43; 2.07); HbA1c ≥78 mmol/mol, aPR 1.42 (95% CI 1.06; 1.88); and antihypertensive drug use, aPR 1.34 (95% CI 1.16; 1.55). Smoking, aPR 1.50 (95% CI 1.24; 1.81), and lack of physical activity (0 vs. ≥3 days/week), aPR 1.61 (95% CI 1.39; 1.85), were also associated with DPN. Smoking, high alcohol intake, and failure to increase activity after diabetes diagnosis associated with neuropathic pain.

CONCLUSIONS

Possible DPN was associated with metabolic syndrome factors, insulin resistance, inflammation, and modifiable lifestyle habits in early type 2 diabetes.




arl

Adolescent Obesity and Early-Onset Type 2 Diabetes

OBJECTIVE

Type 2 diabetes (T2D) is increasingly diagnosed at younger ages. We investigated the association of adolescent obesity with incident T2D at early adulthood.

RESEARCH DESIGN AND METHODS

A nationwide, population-based study evaluated 1,462,362 adolescents (59% men, mean age 17.4 years) during 1996–2016. Data were linked to the Israeli National Diabetes Registry. Weight and height were measured at study entry. Cox proportional models were applied.

RESULTS

During 15,810,751 person-years, 2,177 people (69% men) developed T2D (mean age at diagnosis 27 years). There was an interaction among BMI, sex, and incident T2D (Pinteraction = 0.023). In a model adjusted for sociodemographic variables, the hazard ratios for diabetes diagnosis were 1.7 (95% CI 1.4–2.0), 2.8 (2.3–3.5), 5.8 (4.9–6.9), 13.4 (11.5–15.7), and 25.8 (21.0–31.6) among men in the 50th–74th percentile, 75th–84th percentile, overweight, mild obesity, and severe obesity groups, respectively, and 2.2 (1.6–2.9), 3.4 (2.5–4.6), 10.6 (8.3–13.6), 21.1 (16.0–27.8), and 44.7 (32.4–61.5), respectively, in women. An inverse graded relationship was observed between baseline BMI and mean age of T2D diagnosis: 27.8 and 25.9 years among men and women with severe obesity, respectively, and 29.5 and 28.5 years among low-normal BMI (5th–49th percentile; reference), respectively. The projected fractions of adult-onset T2D that were attributed to high BMI (≥85th percentile) at adolescence were 56.9% (53.8–59.9%) and 61.1% (56.8–65.2%) in men and women, respectively.

CONCLUSIONS

Severe obesity significantly increases the risk for incidence of T2D in early adulthood in both sexes. The rise in adolescent severe obesity is likely to increase diabetes incidence in young adults in coming decades.




arl

Early Metabolic Features of Genetic Liability to Type 2 Diabetes: Cohort Study With Repeated Metabolomics Across Early Life

OBJECTIVE

Type 2 diabetes develops for many years before diagnosis. We aimed to reveal early metabolic features characterizing liability to adult disease by examining genetic liability to adult type 2 diabetes in relation to metabolomic traits across early life.

RESEARCH DESIGN AND METHODS

Up to 4,761 offspring from the Avon Longitudinal Study of Parents and Children were studied. Linear models were used to examine effects of a genetic risk score (162 variants) for adult type 2 diabetes on 229 metabolomic traits (lipoprotein subclass–specific cholesterol and triglycerides, amino acids, glycoprotein acetyls, others) measured at age 8 years, 16 years, 18 years, and 25 years. Two-sample Mendelian randomization (MR) was also conducted using genome-wide association study data on metabolomic traits in an independent sample of 24,925 adults.

RESULTS

At age 8 years, associations were most evident for type 2 diabetes liability (per SD-higher) with lower lipids in HDL subtypes (e.g., –0.03 SD, 95% CI –0.06, –0.003 for total lipids in very large HDL). At 16 years, associations were stronger with preglycemic traits, including citrate and with glycoprotein acetyls (0.05 SD, 95% CI 0.01, 0.08), and at 18 years, associations were stronger with branched chain amino acids. At 25 years, associations had strengthened with VLDL lipids and remained consistent with previously altered traits, including HDL lipids. Two-sample MR estimates among adults indicated persistent patterns of effect of disease liability.

CONCLUSIONS

Our results support perturbed HDL lipid metabolism as one of the earliest features of type 2 diabetes liability, alongside higher branched-chain amino acid and inflammatory levels. Several features are apparent in childhood as early as age 8 years, decades before the clinical onset of disease.




arl

Promising New Research on Early Intervention for Autism

CNN reports that a study confirms that early autism intervention in toddlers is effective. A study was completed with a program called the Early Start Denver Model (ESDM). This program involves about twenty hours a week in the child's own home. It involves play and parents can easily learn some of the skills that can be applied in other settings. The study compared a group of toddlers that were given ESDM intervention to a group of toddlers receiving typical community interventions. Both groups showed improvement, but the ESDM group improved IQ by 18 points compared to 8 points with traditional interventions. The study is reporting that some of the children "virtually caught up to the typical kids their age." However, they are not claiming it is a cure for autism. According to the article they are working on a replication study to determine if there are similar results. Personally, I'm looking forward to the results of the replication study and want to find out more about this method. From what I understand it is less of a time constraint than ABA therapy.

This study also demonstrated the need for early intervention, which also includes early identification. When children are diagnosed early, they can begin receiving interventions that are proven effective. The study showed that current methods are working, but there may be a new program that can be even more effective on the horizon.

I'd love to hear more from my readers if you have any experience with ESDM or more information about it.




arl

Mars' magnetic field emerged earlier and lasted longer than previously thought

Mars' ancient magnetic field emerged earlier and persisted for longer than scientists previously thought, according to a new study.




arl

Early marine reptiles used pebble-like teeth to crush shellfish

Some early ichthyosaurs used rounded, pebble-like teeth to crush the shells of snails and clam-like bivalves, according to new research.




arl

Quality for Whom? Supporting Diverse Children and Workers in Early Childhood Quality Rating and Improvement Systems

For children in U.S. homes where a language other than English is spoken, early childhood programs that are responsive to their needs can be key to later academic success. But as states refine their Quality Rating and Improvement Systems (QRIS) to assess such programs, immigrant early childhood workers with in-demand language and cultural skills may be left behind. This report examines the challenges these workers face and promising practices to serve diverse communities.




arl

Effectively Serving Children in a Superdiverse Classroom: Implications for the Early Education System

As the number and share of Dual Language Learners (DLLs) continues to grow across the United States, diversity within this population is also increasing. This webinar marks the release of a report providing analysis of the diversity within the DLL population nationwide and at the state and local levels. Speakers discuss data on the three rapidly growing subgroups within the DLL population: Black and Asian American and Pacific Islander DLLs and young children of refugees, and the implications for the early education and care field and K-12 education systems. 




arl

Responding to Early Childhood Education and Care Needs of Children of Asylum Seekers and Refugees in Europe and North America

Marking the release of an MPI report, this webinar examines the challenges and successes major host countries in Europe and North America are experiencing in providing high-quality early childhood education and care (ECEC) services for children from refugee and asylum seeker families.




arl

Young Children in Refugee Families and Early Childhood Programs: Ways to Mitigate the Effects of Trauma

Experts on this webinar discussed the effects of trauma on the development of young refugee children, and how early child-care programs can address these traumatic experiences. The discussion featured practical strategies that child-care providers in Canada are implementing to support refugee children and families. 




arl

Addressing Trauma in Young Children in Immigrant and Refugee Families through Early Childhood Programs

During this webinar, speakers discuss a MPI policy brief that explores the intersection of trauma and early childhood development, exploring how migration-related trauma and stressors can influence the wellbeing of young children of immigrants, and points to key opportunities for states to support, through early childhood and other programs.




arl

New Data Resources Can Help Improve Targeting of State Early Childhood and Parent-Focused Programs

As states work to build high-quality early childhood systems and implement the federal Workforce Innovation and Opportunity Act (WIOA) and Every Student Succeeds Act (ESSA), having detailed knowledge of the characteristics of immigrant parents can help maximize the effectiveness of programs that seek to improve child and family outcomes, as this commentary explains.




arl

Introduction to The Old Ways: A Journey on Foot by Robert Macfarlane

My first exposure to Robert Macfarlane happened a year ago when I picked up a battered copy of The Wild Places in order to shelve it. Instead, I checked it out from my branch and stayed up past midnight to read it. Thanks to Macfarlane, I was exposed to Roger Deakin's Wild Wood and Notes from Walnut Tree Farm. I found photos of Walnut Tree Farm, the late Deakin's house, much visited by Macfarlane, while searching for more information about both of them online.

I am from probably the last generation of American children to be raised on English children's books. I know that there is a generation of Quidditch-playing adults that were weaned on the Harry Potter books of British-born J. K. Rowling. While the Harry Potter books are gripping, they lack an essential British characteristic shared by many successful authors of British children's books:

  • Rudyard Kipling - the two Puck of Pook's Hill books
  • Rosemary Sucliff - all of her books
  • Elizabeth Goudge - Rowling helped get Linnets & Valerians and The Little White Horse republished
  • L. M. Boston - the Greene Knowe series
  • William Mayne
  • Robert Westall
  • Diana Wynne Jones - the British landscape of an alternative Britain
  • J. R. R. Tolkein -The Hobbit
  • Kenneth Graham - The Wind in the Willows
  • T. H. White - The Once and Future King
  • Susan Cooper - The Dark is Rising series
I'm sure that there are many more. What these authors and books have in common is a palpable sense of landscape; the English and Welsh earth itself is as present and influential as any of the characters. In any Harry Potter book I had the sense that the only character connected to the land was Hagrid; the rest of the wizards were interested in nature only insofar as they could exploit it for magical potions or familiars.

Both Macfarlane and his late mentor Deakin possessed the same sense of awareness of the land as these children's authors. Deakin kept his hedgerows alive to shelter birds and let animals wander at will through his house. Macfarlane travels, mostly on foot, as he did while he hiked and climbed in both The Wild Places and The Old Ways.




arl

Expansion of legal migration opportunities for third-country nationals, particularly in middle- and low-skill sectors, holds potential but should not be oversold as migration management tool, new study cautions

BRUSSELS — While the European Union has called on Member States to expand channels for foreign workers as a way to meet labour market needs and potentially tackle spontaneous migration, they have struggled to deliver on this pledge. To date, policies have focused more on attracting high-skilled workers, but less attention has been paid to admission of low- or middle-skilled nationals. Policymakers would do well not to overestimate the potential of legal channels to reduce irregular migration.




arl

Badrijani - Grilled Eggplants with a coriander and garlic Aioli

This recipe was featured on Foodie Tuesday, a weekly segment with Raf Epstein on Drive, 774 ABC Melbourne, 3:30 PM, courtesy of Alice in Frames. www.aliceinframes.com