ABSTRACTIntroduction:Family Planning 2020 (FP2020) was established in 2012 with the goal of expanding contraceptive access. By 2020, 46 countries had made commitments to FP2020. A sustained focus on adolescents and youth (AY) began in 2016. During the commitment formulation process, substantial support was offered to countries to develop AY commitments based on sound data, research evidence, and programmatic experience. This study assesses how country commitments under FP2020 and FP2030 have evolved over time with respect to improving attention to and focus on the needs of adolescents and youth sexual and reproductive health (AYSRH).Methods:We analyzed the content of FP2020 and FP2030 country commitments focusing on AY (aged 10–24 years) using a scoring guideline we developed to measure the AY commitments in terms of completeness, clarity, and quality.Results:This analysis shows that FP2030 commitments better articulate strategies and activities to reach AY with contraceptive information and services when compared to FP2020 commitments.Conclusion:FP2030 commitments are stronger in some areas on AYSRH, such as commitment to establish national or local policies, strategies, and guidance for AY programming, specifying the target audience of the AY commitment, and partnering with AY or youth-led organizations in commitments. However, more work remains to be done by countries to dedicate a budget for achieving AY objectives, including measurable targets for monitoring progress, identifying and addressing the root causes that impact AY access to and use of contraception, including child marriage and gender-based violence, and reducing financial barriers to access contraception.

ABSTRACTIn the Democratic Republic of the Congo (DRC), male engagement, social norms, and social networks mitigate family planning behavior. We discuss the adaptation of the Social Norms Exploration Tool (SNET), which identifies relevant social norms and community members upholding these norms, to inform the development of family planning interventions in the DRC. The SNET provides activity tools and templates to guide users through the following steps: (1) plan and prepare, (2) identify reference groups, (3) explore social norms, (4) analyze results, and (5) apply findings.The SNET approach resulted in discussion of social norms, particularly around birth spacing and gender norms framing the man as the decision-maker. However, despite applying a methodology specifically designed to identify social norms, other factors limiting use of contraceptive methods were identified in the process, including lack of education, rumors, and misconceptions. Adaptations were needed to include the full range of reference groups due to narrow phrasing of primary questions, and some of the participatory methods were overly complicated. Feedback from experienced data collectors suggested that the social norms framework is not intuitive, is difficult to apply correctly, and may require that data collectors have a stronger foundation in the relevant concepts to produce valid and actionable results.Although the SNET provides language for discussing normative factors and techniques to identify reference groups and social norms, modifications to the implementation process are recommended when adapting the tool for research.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS), with a putative autoimmune origin and complex pathogenesis. Modification of the natural history of MS by reducing relapses and slowing disability accumulation was first attained in the 1990 s with the development of the first-generation disease-modifying therapies. Glatiramer acetate (GA), a copolymer of L-alanine, L-lysine, L-glutamic acid, and L-tyrosine, was discovered due to its ability to suppress the animal model of MS, experimental autoimmune encephalomyelitis. Extensive clinical trials and long-term assessments established the efficacy and the safety of GA. Furthermore, studies of the therapeutic processes induced by GA in animal models and in MS patients indicate that GA affects various levels of the innate and the adaptive immune response, generating deviation from proinflammatory to anti-inflammatory pathways. This includes competition for binding to antigen presenting cells; driving dendritic cells, monocytes, and B-cells toward anti-inflammatory responses; and stimulating T-helper 2 and T-regulatory cells. The immune cells stimulated by GA reach the CNS and secrete in situ anti-inflammatory cytokines alleviating the pathological processes. Furthermore, cumulative findings reveal that in addition to its immunomodulatory effect, GA promotes neuroprotective repair processes such as neurotrophic factors secretion, remyelination, and neurogenesis. This review aims to provide an overview of MS pathology diagnosis and treatment as well as the diverse mechanism of action of GA.

BACKGROUND AND PURPOSE:

Neuronal ceroid lipofuscinoses are a group of neurodegenerative disorders. Recently, enzyme replacement therapy (ERT) was approved for neuronal ceroid lipofuscinosis type 2 (CLN2), a subtype of neuronal ceroid lipofuscinoses. The aim of this study was to quantify brain volume loss in CLN2 disease in patients on ERT in comparison with a natural history cohort using MRI.

Dihydropyrimidinase (DHP) deficiency is an autosomal recessive metabolic disorder caused by biallelic pathogenic variants of DPYS. Patients with DHP deficiency exhibit a broad spectrum of phenotypes, ranging from severe neurological and gastrointestinal involvement to cases with no apparent symptoms. The biochemical diagnosis of DHP deficiency is based on the detection of a significant amount of dihydropyrimidines in urine, plasma, and cerebrospinal fluid samples. Molecular genetic testing, specifically the identification of biallelic pathogenic variants in DPYS, has proven instrumental in confirming the diagnosis and facilitating family studies. This case study documents the diagnostic journey of an 18-yr-old patient with DHP deficiency, highlighting features at the severe end of the clinical spectrum. Notably, our patient exhibited previously unreported skeletal features that positively responded to bisphosphonate treatment, contributing valuable insights to the clinical characterization of DHP deficiency. Additionally, a novel DPYS variant was identified and confirmed pathogenicity through metabolic testing, further expanding the variant spectrum of the gene. Our case emphasizes the importance of a comprehensive diagnostic approach using genetic sequencing and metabolic testing for accurate diagnosis.

We present a unique case of a single patient presenting with two mutationally distinct, PD-L1⁺ diffuse large B-cell lymphomas (DLBCLs). One of these DLBCLs demonstrated exceptionally high mutational burden (eight disease-associated variants and 41 variants of undetermined significance) with microsatellite instability (MSI) and an acquired PMS2 mutation with loss of PMS2 protein expression, detected postchemotherapy. This report, while highlighting the extent of possible tumor heterogeneity across separate clonal expansions as well as possible syndromic B-cell neoplasia, supports the notion that, although rare, PD-L1 expression and associated states permissive of high mutational burden (such as mismatch repair gene loss of function/MSI) should be more routinely considered in DLBCLs. Appropriate testing may be predictive of outcome and inform the utility of targeted therapy in these genetically diverse and historically treatment-refractory malignancies.

Although the progressive histologic steps leading to endometrial cancer (EndoCA), the most common female reproductive tract malignancy, from endometrial hyperplasia are well-established, the molecular changes accompanying this malignant transformation in a single patient have never been described. We had the unique opportunity to investigate the paired histologic and molecular features associated with the 12-yr development of EndoCA in a postmenopausal female who could not undergo hysterectomy and instead underwent progesterone treatment. Using a specially designed 58-gene next-generation sequencing panel, we analyzed a total of 10 sequential biopsy samples collected over this time frame. A total of eight pathogenic/likely pathogenic mutations in seven genes, APC, ARID1A, CTNNB1, CDKN2A, KRAS, PTEN, and TP53, were identified. A PTEN nonsense mutation p.W111* was present in all samples analyzed except histologically normal endometrium. Apart from this PTEN mutation, the only other recurrent mutation was KRAS G12D, which was present in six biopsy samplings, including histologically normal tissue obtained at the patient's first visit but not detectable in the cancer. The PTEN p.W111* mutant allele fractions were lowest in benign, inactive endometrial glands (0.7%), highest in adenocarcinoma (36.9%), and, notably, were always markedly reduced following progesterone treatment. To our knowledge, this report provides the first molecular characterization of EndoCA development in a single patient. A single PTEN mutation was present throughout the 12 years of cancer development. Importantly, and with potential significance toward medical and nonsurgical management of EndoCA, progesterone treatments were consistently noted to markedly decrease PTEN mutant allele fractions to precancerous levels.

Metastatic porocarcinomas (PCs) are vanishingly rare, highly aggressive skin adnexal tumors with mortality rates exceeding 70%. Their rarity has precluded the understanding of their disease pathogenesis, let alone the conduct of clinical trials to evaluate treatment strategies. There are no effective agents for unresectable PCs. Here, we successfully demonstrate how functional precision medicine was implemented in the clinic for a metastatic PC with no known systemic treatment options. Comprehensive genomic profiling of the tumor specimen did not yield any actionable genomic aberrations. However, ex vivo drug testing predicted pazopanib efficacy, and indeed, administration of pazopanib elicited remarkable clinicoradiological response. Pazopanib and its class of drugs should be evaluated for efficacy in other cases of PC, and the rationale for efficacy should be determined when PC tumor models become available. A functional precision medicine approach could be useful to derive effective treatment options for rare cancers.

The diagnosis of maturity-onset diabetes of the young (MODY), a monogenic form of diabetes mellitus caused by a mutation in a single gene, is often uncertain until genetic testing is performed. We report a 13-yr-old Korean boy who was initially diagnosed with type 2 diabetes (T2DM). MODY was suspected because of his nonobese body habitus and family history of multiple affected members. Targeted panel sequencing of all MODY-related genes was performed using the NextSeq 550Dx platform (Illumina). Sanger sequencing was performed using blood samples from the parents, siblings, and other relatives. A frameshift variant in the 3' region of the last exon of PDX1 was detected in the patient and his family members with diabetes. PP1_Moderate criterion was applied and this variant was confirmed to be the genetic cause of diabetes in the family and classified as likely pathogenic. The study highlights the importance of genetic testing for nonobese, early-onset diabetic patients with multiple affected family members. Increased awareness and aggressive genetic testing for MODY are needed.

Veterans are at an increased risk for prostate cancer, a disease with extraordinary clinical and molecular heterogeneity, compared with the general population. However, little is known about the underlying molecular heterogeneity within the veteran population and its impact on patient management and treatment. Using clinical and targeted tumor sequencing data from the National Veterans Affairs health system, we conducted a retrospective cohort study on 45 patients with advanced prostate cancer in the Veterans Precision Oncology Data Commons (VPODC), most of whom were metastatic castration-resistant. We characterized the mutational burden in this cohort and conducted unsupervised clustering analysis to stratify patients by molecular alterations. Veterans with prostate cancer exhibited a mutational landscape broadly similar to prior studies, including KMT2A and NOTCH1 mutations associated with neuroendocrine prostate cancer phenotype, previously reported to be enriched in veterans. We also identified several potential novel mutations in PTEN, MSH6, VHL, SMO, and ABL1. Hierarchical clustering analysis revealed two subgroups containing therapeutically targetable molecular features with novel mutational signatures distinct from those reported in the Catalogue of Somatic Mutations in Cancer database. The clustering approach presented in this study can potentially be used to clinically stratify patients based on their distinct mutational profiles and identify actionable somatic mutations for precision oncology.

Electron transport chain (ETC) disorders are a group of rare, multisystem diseases caused by impaired oxidative phosphorylation and energy production. Deficiencies in complex III (CIII), also known as ubiquinol–cytochrome c reductase, are particularly rare in humans. Ubiquinol–cytochrome c reductase core protein 2 (UQCRC2) encodes a subunit of CIII that plays a crucial role in dimerization. Several pathogenic UQCRC2 variants have been identified in patients presenting with metabolic abnormalities that include lactic acidosis, hyperammonemia, hypoglycemia, and organic aciduria. Almost all previously reported UQCRC2-deficient patients exhibited neurodevelopmental involvement, including developmental delays and structural brain anomalies. Here, we describe a girl who presented at 3 yr of age with lactic acidosis, hyperammonemia, and hypoglycemia but has not shown any evidence of neurodevelopmental dysfunction by age 15. Whole-exome sequencing revealed compound heterozygosity for two novel variants in UQCRC2: c.1189G>A; p.Gly397Arg and c.437T>C; p.Phe146Ser. Here, we discuss the patient's clinical presentation and the likely pathogenicity of these two missense variants.

Alveolar capillary dysplasia (ACD) is a fatal disorder that typically presents in the neonatal period with refractory hypoxemia and pulmonary hypertension. Lung biopsy is traditionally required to establish the diagnosis. We report a 22-mo-old male who presented with anemia, severe pulmonary hypertension, and right heart failure. He had a complicated hospital course resulting in cardiac arrest and requirement for extracorporeal membrane oxygenation. Computed tomography of the chest showed a heterogenous pattern of interlobular septal thickening and pulmonary edema. The etiology of his condition was unknown, lung biopsy was contraindicated because of his medical fragility, and discussions were held to move to palliative care. Rapid whole-genome sequencing (rWGS) was performed. In 2 d it resulted, revealing a novel FOXF1 gene pathogenic variant that led to the presumptive diagnosis of atypical ACD. Cases of atypical ACD have been reported with survival in patients using medical therapy or lung transplantation. Based on the rWGS diagnosis and more favorable potential of atypical ACD, aggressive medical treatment was pursued. The patient was discharged home after 67 d in the hospital; he is currently doing well more than 30 mo after his initial presentation with only one subsequent hospitalization and no requirement for lung transplantation. Our case reveals the potential for use of rWGS in a critically ill child in which the diagnosis is unknown. rWGS and other advanced genetic tests can guide clinical management and expand our understanding of atypical ACD and other conditions.

Here, we highlight the case of a 31-yr-old man who had clinical features of primary hypertrophic osteoarthropathy (PHOAR) and harbored a homozygous variant (c.38C > A, p.Ala13Glu) in the HPGD gene, as indicated by whole-exome sequencing (WES). This variant has been previously classified by our laboratory as a variant of uncertain significance (VUS). However, another patient with the same phenotype and the same homozygous variant in HPGD was subsequently reported. In reassessing the variant, the absence of this variant in the gnomAD population database, supporting computational predictions, observation in homozygosity in two probands, and specificity of the phenotype for HPGD, all provide sufficient evidence to reclassify the HPGD c.38C > A, p.Ala13Glu variant as likely pathogenic.

The usual challenges of conducting primary care research, including randomized trials, have been exacerbated, and new ones identified, during the COVID-19 pandemic. HOMER (Home versus Office for Medication Enhanced Recovery; subsequently, Comparing Home, Office, and Telehealth Induction for Medication Enhanced Recovery) is a pragmatic, comparative-effectiveness research trial that aims to answer a key question from patients and clinicians: What is the best setting in which to start treatment with buprenorphine for opioid use disorder for this patient at this time? In this article, we describe the difficult journey to find the answer. The HOMER study began as a randomized trial comparing treatment outcomes in patients starting treatment with buprenorphine via induction at home (unobserved) vs in the office (observed, synchronous). The study aimed to enroll 1,000 participants from 100 diverse primary care practices associated with the State Networks of Colorado Ambulatory Practices and Partners and the American Academy of Family Physicians National Research Network. The research team faced unexpected challenges related to the COVID-19 pandemic and dramatic changes in the opioid epidemic. These challenges required changes to the study design, protocol, recruitment intensity, and funding conversations, as well as patience. As this is a participatory research study, we sought, documented, and responded to practice and patient requests for adaptations. Changes included adding a third study arm using telehealth induction (observed via telephone or video, synchronous) and switching to a comprehensive cohort design to answer meaningful patient-centered research questions. Using a narrative approach based on the Greek myth of Homer, we describe here the challenges and adaptations that have provided the opportunity for HOMER to thrive and find the way home. These clinical trial strategies may apply to other studies faced with similar cultural and extreme circumstances.

PURPOSE

HIV pre-exposure prophylaxis (PrEP) may increase rates of bacterial sexually transmitted infections (STIs) among gay, bisexual, and other men who have sex with men (GBM) through risk compensation (eg, an increase in condomless sex or number of partners); however, longitudinal studies exploring the time-dependent nature of PrEP uptake and bacterial STIs are limited. We used marginal structural models to estimate the effect of PrEP uptake on STI incidence.

PURPOSE

Despite being key to better health outcomes for patients from racial and ethnic minority groups, the proportion of underrepresented in medicine (URiM) physicians remains low in the US health care system. This study linked a nationally representative sample of family physicians (FPs) with Medicaid claims data to explore the relative contributions to care of Medicaid populations by FP race and ethnicity.

The strength of reproductive isolation (RI) between two or more lineages during the process of speciation can vary by the ecological conditions. However, most speciation research has been limited to studying how ecologically dependent RI varies among a handful of broadly categorized environments. Very few studies consider the variability of RI and its effects on speciation at finer scales—that is, within each environment due to spatial or temporal environmental heterogeneity. Such variation in RI across time and/or space may inhibit speciation through leaky reproductive barriers or promote speciation by facilitating reinforcement. To investigate this overlooked aspect of speciation research, we conducted a literature review of existing studies of variation in RI in the field and then conducted individual-based simulations to examine how variation in hybrid fitness across time and space affects the degree of gene flow. Our simulations indicate that the presence of variation in hybrid fitness across space and time often leads to an increase in gene flow compared to scenarios where hybrid fitness remains static. This observation can be attributed to the convex relationship between the degree of gene flow and the strength of selection on hybrids. Our simulations also show that the effect of variation in RI on facilitating gene flow is most pronounced when RI, on average, is relatively low. This finding suggests that it could serve as an important mechanism to explain why the completion of speciation is often challenging. While direct empirical evidence documenting variation in extrinsic RI is limited, we contend that it is a prevalent yet underexplored phenomenon. We support this argument by proposing common scenarios in which RI is likely to exhibit variability and thus influence the process of speciation.

It will likely release in 2026 and feature Apple Intelligence, according to a reliable analyst.

In August, fellow reporter Jason Patinkin and I crossed on foot from northern Uganda into rebel-held South Sudan. Over the course of four days, we walked more than 40 miles through the bush, escorted by rebel soldiers, to shed light on one of the world’s most underreported conflicts.

Reporting on South Sudan’s war, which began in 2013, has always been a challenge due to the risk and logistical hurdles associated with accessing remote areas where fighting takes place. But over the past year, covering the war and its humanitarian fallout has become particularly difficult. Since the beginning of this year, South Sudan’s government has banned at least 20 foreign journalists in an apparent effort to silence reporters who had a track record of critically reporting on the government.

This systematic crackdown on the foreign press (South Sudanese journalists have long risked imprisonment and death for doing their work) coincided with two important developments. In November 2016, the United Nations warned that the violence being committed against civilians in the southern region of Equatoria risked spiraling into genocide. Then, in February, the UN declared a man-made famine, warning that 100,000 people were at risk of starving to death as a result of civil war.

Journalists seeking to cover these events were left with two equally unsavory options: self-censorship or a risky trip to rebel-held parts of the country. Only a handful of journalists have attempted the latter since fighting escalated in July last year. For us, this was our second embed with the rebels this year.

We set off from a town in northern Uganda at five in the morning, bouncing along a bumpy dirt track towards the South Sudan border. Crammed into our four-wheel drive were rebel commander Martin Abucha, a dual American and South Sudanese citizen who we planned to profile for our PBS NewsHour Weekend segment, a couple of guides, and several duffle bags stuffed with our tents, sleeping bags, emergency medical kits and provisions to last us four days.

Just as the sun began to rise above a distant range of hills that we aimed to cross later that day, our car came to a halt in front of a stream. Because of the rainy reason, it carried more water than usual. It was time to disembark and start walking, or “footing,” as South Sudanese tend to call it.

We took off our shoes and waded through the stream’s chilly waters. This was the first of a many rivers we’d have to cross along the way, either on foot or in small flimsy canoes dug out from tree trunks. Each time, we dreaded the idea of falling in with our camera gear.

The first part of our journey in northern Uganda felt very much like a hike through a national park. Passing beautiful landscapes and idyllic farming villages, one could almost forget we were headed into a war zone — but we were about to get a reality check.

We had just crossed into South Sudan when out of nowhere, two dozen armed men popped out of the tall grass and surrounded us at gunpoint.

“Stop! Who are you and where are you going?” a soldier called out in Juba Arabic from his hideout no more than 20 yards away, pointing his AK47 at us. Another one next to him had a rocket-propelled grenade propped on his shoulder, also unequivocally aiming it in our direction.

Instinctively, we threw our hands in the air and exchanged a baffled glance. Had we accidentally bumped into government soldiers? Or perhaps we had come onto the “wrong” rebels? Abucha’s group, called the Sudan People’s Liberation Army In Opposition, is the biggest but not the only armed group in Equatoria, an area rife with rival militia and bandits who exploit the security vacuum left by war.

To our relief, and only after Abucha answered a series of questions, this routine security check quickly gave way to a warm welcome. The platoon would be our escort for the next four days as we trekked to their base and to Loa, Abucha’s hometown.

Keeping up with the rebels was no easy task. Given the country’s pervasive lack of basic infrastructure, South Sudanese grow up walking for dozens of miles just to go about their daily lives. For sedentary Westerners, keeping the target pace of “two meters per second” (around five miles an hour) proved challenging amid 90-degree temperatures, all while filming and plowing our way through dense, itchy elephant grass.

The upside of the cumbersome terrain was that it kept us safe. During our four-day trip, we didn’t cross a single road, instead walking along a dizzying network of narrow bush paths the rebels seemed to know like the backs of their hands. An unwanted encounter with government troops, who tended to stick to roads and move around in vehicles as opposed to on foot, was highly unlikely.

The closest we got to government-controlled area was a visit to Loa, located just two kilometers away from a main road frequently patrolled by government soldiers. We couldn’t stay long, but the hour we spent on the ground offered us a glimpse into what villages must look like in many parts of Equatoria: burned mud huts, looted schools and clinics, fallow fields and – most strikingly – no civilians.

The war has had a devastating impact on South Sudanese communities like the one in Loa, but much of it has remained out of the limelight of international media. Our four-day venture into rebel-held South Sudan offered us a rare opportunity to report ground truths, and we are thankful for that.

The post Column: Why reporting from South Sudan is so difficult — and critically needed appeared first on PBS NewsHour.

Secretary of State Rex Tillerson speaks at the Center for Strategic and International Studies on Wednesday.

WASHINGTON — Secretary of State Rex Tillerson is condemning reported atrocities committed against Rohingya Muslims in Myanmar, and he says those responsible — perhaps the country’s military — will be held accountable.

Tillerson says accounts of the suffering of the Rohingya are “heartbreaking” — and that if those reports are true, then “someone is going to be held to account for that.”

Tillerson — who’s set to visit South Asia next week — is urging the Myanmar government to improve humanitarian access to the population in western Rakhine state.

Amnesty International has accused Myanmar’s security forces of killing hundreds of men, women and children during a systematic campaign to expel the Rohingya. More than 580,000 refugees have fled to neighboring Bangladesh since late August.

“We really hold the military leadership accountable for what’s happening,” Tillerson said at the Center for Strategic and International Studies, a Washington think tank. “What’s most important to us is that the world can’t just stand idly by and be witness to the atrocities that are being reported in that area.”

He also called Wednesday for the U.S. and India to expand strategic ties. He pointedly criticized China, which he accused of challenging international norms needed for global stability.

He said the world needed the U.S. and India to have a strong partnership. The two nations share goals of security, free navigation, free trade and fighting terrorism in the Indo-Pacific, and serve as “the eastern and western beacons” for an international rules-based order which is increasingly under strain, he said.

Both India and China had benefited from that order, but Tillerson said India had done so while respecting rules and norms, while China had “at times” undermined them. To make his point, he alluded to China’s island building and expansive territorial claims in seas where Beijing has long-running disputes with Southeast Asian neighbors.

“China’s provocative actions in the South China Sea directly challenge the international law and norms that the United States and India both stand for,” Tillerson said in an address at the Center for Strategic and International Studies, a Washington think tank.

He added that the U.S. seeks constructive relations with China but “won’t shrink” from the challenges it poses when it “subverts the sovereignty of neighboring countries, and disadvantages the U.S. and our friends.”

U.S.-India relations have generally prospered in the past decade, in part because of their shared concerns about the rise of China. While President Donald Trump has looked to deepen cooperation with China on addressing the nuclear threat from North Korea, he’s also sought a closer relationship with India, which shares U.S. worries on Islamic extremism.

“In this period of uncertainty and angst, India needs a reliable partner on the world stage. I want to make clear: with our shared values and vision for global stability, peace and prosperity, the United States is that partner,” Tillerson said.

Tillerson said the U.S. wants to help improve India’s military capabilities, and also improve security cooperation among the region’s major democracies, which included Japan and Australia.

Tillerson said the U.S. and India were leading regional efforts on counterterrorism. He called for India’s archrival Pakistan “to take decisive action against terrorist groups based within their own borders that threaten its own people and the broader region.”

The post Tillerson: ‘Heartbreaking’ reports of suffering in Myanmar appeared first on PBS NewsHour.

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… advice from former New Zealand Davis Cup player Dan Willman, who has … challenges Taranaki for the Christie Cup, the symbol of Central … place at the World Junior Davis Cup tournament in the Czech … ; Willman added. The Christie Cup has been played for since ….

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In its annual report, the Food Safety Authority of Ireland (FSAI) warned that food incidents are becoming more complex and often serious. FSAI marked its 25th anniversary in 2023. External challenges impacting food safety include the potential for supply disruption due to political unrest in the Middle East and the... Continue Reading

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