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Anatomically modern humans (Homo sapiens, AMH) began spreading across Eurasia from Africa and adjacent Southwest Asia about 50,000–55,000 years ago (ca. 50–55 ka). Some have argued that human genetic, fossil, and archaeological data indicate one or more prior dispersals, possibly as early as 120 ka. A recently reported age estimate of 65 ka for Madjedbebe, an archaeological site in northern Sahul (Pleistocene Australia–New Guinea), if correct, offers what might be the strongest support yet presented for a pre–55-ka African AMH exodus. We review evidence for AMH arrival on an arc spanning South China through Sahul and then evaluate data from Madjedbebe.We find that an age estimate of >50 ka for this site is unlikely to be valid. While AMH may have moved far beyond Africa well before 50–55 ka, data from the region of interest offered in support of this idea are not compelling.

Tumour necrosis factor (TNF) is a trimeric protein which signals through two membrane receptors, TNFR1 and TNFR2. Previously, we identified small molecules that inhibit human TNF by stabilising a distorted trimer and reduce the number of receptors bound to TNF from three to two. Here we present a biochemical and structural characterisation of the small molecule-stabilised TNF-TNFR1 complex, providing insights into how a distorted TNF trimer can alter signalling function. We demonstrate that the inhibitors reduce the binding affinity of TNF to the third TNFR1 molecule. In support of this, we show by X-ray crystallography that the inhibitor-bound, distorted, TNF trimer forms a complex with a dimer of TNFR1 molecules. This observation, along with data from a solution-based network assembly assay, leads us to suggest a model for TNF signalling based on TNF-TNFR1 clusters, which are disrupted by small molecule inhibitors. Small molecules stabilising a distorted TNF trimer can inhibit TNF signaling, but the underlying mechanism is unclear. Here, the authors characterize the inhibitor-bound TNF-receptor complex structurally and biochemically, showing that the inhibitors alter TNF-receptor binding stoichiometry and cluster formation.

Advocates claim that providing permanent supportive housing to chronically homeless people will deliver net savings by reducing the use of jails, shelters, and hospitals. It won't. Rather than focus on costs, we should consider the best way to meet this population's needs. The persistence of homelessness in the United States has increased interest in providing permanent housing with supportive services to people with disabling conditions who have been homeless for more than a year. Skeptical about achieving political consensus on providing housing solely on humanitarian grounds, advocates for ending homelessness have increasingly turned to a financial argument, claiming that permanent supportive housing will deliver net cost savings to society by reducing the use of jails, shelters, and hospitals. But as researchers and clinicians who endorse such permanent supportive housing, we believe the cost-savings argument is problematic and that it would be better . . .

People experiencing homelessness are at high risk for coronavirus disease 2019 (COVID-19). In March 2020, Boston Health Care for the Homeless Program, in partnership with city and state public health agencies, municipal leaders, and homeless service providers, developed and implemented a citywide COVID-19 care model for this vulnerable population. Components included symptom screening at shelter front doors, expedited testing at pop-up sites, isolation and management venues for symptomatic people under investigation and for people with confirmed disease, quarantine venues for asymptomatic exposed people, and contact investigation and tracing. Real-time disease surveillance efforts in a large shelter outbreak of COVID-19 during the third week of operations illustrated the need for several adaptations to the care model to better respond to the local epidemiology of illness among people experiencing homelessness. Symptom screening was de-emphasized given the high number of asymptomatic or minimally symptomatic infections discovered during mass testing; contact tracing and quarantining were phased out under the assumption of universal exposure among the sheltered population; and isolation and management venues were rapidly expanded to accommodate a surge in people with newly diagnosed COVID-19. During the first 6 weeks of operation, 429 of 1297 (33.1%) tested people were positive for COVID-19; of these, 395 people were experiencing homelessness at the time of testing, representing about 10% of the homeless adult population in Boston. Universal testing, as resources permit, is a focal point of ongoing efforts to mitigate the effect of COVID-19 on this vulnerable group of people.

Objectives. We quantified tobacco-, alcohol-, and drug-attributable deaths and their contribution to mortality disparities among homeless adults. Methods. We ascertained causes of death among 28 033 adults seen at the Boston Health Care for the Homeless Program in 2003 to 2008. We calculated population-attributable fractions to estimate the proportion of deaths attributable to tobacco, alcohol, or drug use. We compared attributable mortality rates with those for Massachusetts adults using rate ratios and differences. Results. Of 1302 deaths, 236 were tobacco-attributable, 215 were alcohol-attributable, and 286 were drug-attributable. Fifty-two percent of deaths were attributable to any of these substances. In comparison with Massachusetts adults, tobacco-attributable mortality rates were 3 to 5 times higher, alcohol-attributable mortality rates were 6 to 10 times higher, and drug-attributable mortality rates were 8 to 17 times higher. Disparities in substance-attributable deaths accounted for 57% of the all-cause mortality gap between the homeless cohort and Massachusetts adults. Conclusions. In this clinic-based cohort of homeless adults, over half of all deaths were substance-attributable, but this did not fully explain the mortality disparity with the general population. Interventions should address both addiction and non-addiction sources of excess mortality.

The Republic of Ireland (ROI) has a low incidence of TB. A reform of TB services in 2003 recommended that the delivery of care to patients with TB should primarily be in the outpatient setting, with limited indications for hospitalization. Three hospitals were designated as TB centres. Our aim was to describe the utilization of hospital inpatient care by patients with TB in the ROI. We searched public hospital coding data to identify discharges between 01/01/2015-31/12/18 where TB was the principal diagnosis. The cost of TB episodes of care was calculated using payment rules for public hospitals in the ROI. We identified 1185 discharges with TB as the principal diagnosis. Of these, 68% (801/1185) were emergency episodes of care and 32% (384/1185) were elective. We estimate that 65.1% (818/1257) patients with TB notified in the ROI from 2015 to 2018 who had an episode of care in a public hospital was 65.1% (818/1257) and that 50.8% (639/1257) of those notified had an emergency episode of care. The estimated mean annual cost of TB inpatient care per year in the ROI from 2015 to 2018 was €2,638,828-2,955,047, with emergency episodes of care having a mean annual cost of €2,250,926-2,557,397 per year. The burden of TB on hospital inpatient care in the Republic of Ireland is significant.

Automation using geolocation tracking allowed South Korea to trace contacts of people infected with SARS-CoV-2 reaching back to 14 days before symptom onset or diagnosis. By the end of 2020, there were at least 65 advanced digital contact-tracing systems worldwide.

Tumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn’s disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein–protein interactions. While biologics have been successfully applied in TNF antagonist treatments, there are no clinically approved small molecules that target TNF. Here, the authors discover potent small molecule inhibitors of TNF, elucidate their molecular mechanism, and demonstrate TNF inhibition in vitro and in vivo.

We have recently described the development of a series of small-molecule inhibitors of human tumour necrosis factor (TNF) that stabilise an open, asymmetric, signalling-deficient form of the soluble TNF trimer. Here, we describe the generation, characterisation, and utility of a monoclonal antibody that selectively binds with high affinity to the asymmetric TNF trimer–small molecule complex. The antibody helps to define the molecular dynamics of the apo TNF trimer, reveals the mode of action and specificity of the small molecule inhibitors, acts as a chaperone in solving the human TNF–TNFR1 complex crystal structure, and facilitates the measurement of small molecule target occupancy in complex biological samples. We believe this work defines a role for monoclonal antibodies as tools to facilitate the discovery and development of small-molecule inhibitors of protein–protein interactions. TNF can be inhibited by small molecules that stabilize the TNF trimer in an asymmetric conformation. Here, the authors develop a monoclonal antibody that selectively binds this inactive form of TNF, enabling both target engagement assessment and structural characterization of TNF binding to TNF receptor 1.