Adherence Measured Using Electronic Dose Monitoring is Associated with Emergent Antiretroviral Resistance and Poor Outcomes in People with Human Immunodeficiency Virus/AIDS and Multidrug-Resistant Tuberculosis.

BACKGROUND: Medication adherence is known to challenge treatment of human immunodeficiency virus (HIV)/AIDS and multidrug-resistant tuberculosis (MDR-TB). We hypothesized that adherence using electronic dose monitoring (EDM) would identify an antiretroviral therapy (ART) adherence threshold for emergent ART resistance and predict treatment outcomes in patients with MDR-TB and HIV on ART and bedaquiline-containing TB regimens. METHODS: A prospective cohort of adults with MDR-TB and HIV on ART and initiating MDR-TB treatment with bedaquiline were enrolled at a public hospital in KwaZulu-Natal, South Africa (PRAXIS Study). Participants received separate EDM devices that measure adherence to bedaquiline and ART (nevirapine or lopinavir/ritonavir). Adherence was calculated cumulatively over 6 months. Participants were followed through completion of MDR-TB treatment. HIV genome sequencing was performed at baseline and 2 and 6 months on samples with HIV RNA ≥1000 copies/mL. RESULTS: From November 2016 through February 2018, 198 persons with MDR-TB and HIV were enrolled and followed (median, 17.2 months; interquartile range, 12.2-19.6). Eleven percent had baseline ART resistance mutations, and 7.5% developed emergent ART resistance at 6 months. ART adherence was independently associated with ART resistance and mortality. Modeling identified a significant (P < .001), linear association between ART adherence and emergent resistance, suggesting a strong association without a specific threshold. CONCLUSIONS: Our findings highlight the need for ART resistance testing, especially in patients with MDR-TB and HIV, which is currently not the standard of care in resource-limited settings. Despite short follow-up duration, reduced ART adherence was significantly associated with emergent resistance and increased mortality. CLINICAL TRIALS REGISTRATION: NCT03162107.

Directly Transmitted 12.3-Mb Deletion with a Consistent Phenotype in the Variable 11q21q22.3 Region.

A phenotype is emerging for the proximal pair of G-dark bands in 11q (11q14.1 and q14.3) but not yet for the distal pair (11q22.1 and q22.3). A mother and daughter with the same directly transmitted 12.3-Mb interstitial deletion of 11q21q22.3 (GRCh37: 93,551,765-105,817,723) both had initial feeding difficulties and failure to thrive, speech delay, learning difficulties, and mild dysmorphism. Among 17 patients with overlapping deletions, developmental or speech delay, dysmorphism, hypotonia, intellectual disability or learning difficulties, short stature, and coloboma were each found in 2 or more. These results may provide the basis for a consistent phenotype for this region. Among the 53 deleted and additional breakpoint genes, CNTN5, YAP1, and GRI4 were the most likely candidates. Non-penetrance of haploinsufficient genes and dosage compensation among related genes may account for the normal cognition in the mother and variable phenotypes that can extend into the normal range.

Incomplete penetrance, variable expressivity, or dosage insensitivity in four families with directly transmitted unbalanced chromosome abnormalities.

The direct transmission of microscopically visible unbalanced chromosome abnormalities (UBCAs) is rare and usually has phenotypic consequences. Here we report four families in which a normal phenotype was initially found in one or more family members. Each UBCA was interpreted with regard to overlapping examples and factors previously associated with transmitted imbalances including incidental ascertainment, low gene density, benign copy number variation (CNV) content, and gene relatedness. A 4.56 Mb deletion of 8p23.1-p23.2 was thought to be causal in the affected proband but showed incomplete penetrance in her mother and sibling (Family 1). Incomplete penetrance was also associated with a 10.88 Mb duplication of 13q21.31-q22.1 (Family 3) and dosage insensitivity with a 17.6 Mb deletion of 22pter-q11.21 (Family 4) that were both ascertained at prenatal diagnosis and each found in 4 unaffected family members. The 22pter-q11.21 deletion is part of a region with high benign CNV content and supports the mapping of cat eye syndrome to a 600 kb interval of 22q11.1-q11.21. Low gene densities of less than 2.0 genes/Mb were found in each of these three families but only after segmentally duplicated genes were excluded from the deletions of 8p and 22q. In contrast, gene density was average and variable expressivity associated with a 3.59 Mb duplication of 8p23.1 incidentally ascertained for paternal infertility (Family 2). Our results indicate that a greater degree of direct parental transmission, incomplete penetrance, and variable expression are features of both sub-microscopic CNVs and UBCAs with relatively low gene and high benign CNV content.

Identification of Younger Dryas outburst flood path from Lake Agassiz to the Arctic Ocean.

The melting Laurentide Ice Sheet discharged thousands of cubic kilometres of fresh water each year into surrounding oceans, at times suppressing the Atlantic meridional overturning circulation and triggering abrupt climate change. Understanding the physical mechanisms leading to events such as the Younger Dryas cold interval requires identification of the paths and timing of the freshwater discharges. Although Broecker et al. hypothesized in 1989 that an outburst from glacial Lake Agassiz triggered the Younger Dryas, specific evidence has so far proved elusive, leading Broecker to conclude in 2006 that "our inability to identify the path taken by the flood is disconcerting". Here we identify the missing flood path-evident from gravels and a regional erosion surface-running through the Mackenzie River system in the Canadian Arctic Coastal Plain. Our modelling of the isostatically adjusted surface in the upstream Fort McMurray region, and a slight revision of the ice margin at this time, allows Lake Agassiz to spill into the Mackenzie drainage basin. From optically stimulated luminescence dating we have determined the approximate age of this Mackenzie River flood into the Arctic Ocean to be shortly after 13,000 years ago, near the start of the Younger Dryas. We attribute to this flood a boulder terrace near Fort McMurray with calibrated radiocarbon dates of over 11,500 years ago. A large flood into the Arctic Ocean at the start of the Younger Dryas leads us to reject the widespread view that Agassiz overflow at this time was solely eastward into the North Atlantic Ocean.

Inside the 8p23.1 duplication syndrome; eight microduplications of likely or uncertain clinical significance.

The 8p23.1 duplication syndrome (8p23.1 DS) is a recurrent genomic condition with an estimated prevalence of 1 in 58,000. The core 3.68 Mb duplication contains 32 genes of which five are currently candidates for the phenotypic features. Here we describe four patients and five families with eight microduplications of 8p23.1 ranging from 187 to 1082 kb in size and one atypical duplication of 4 Mb. These indicate that a minimal region of overlap (MRO) in medial 8p23.1 can give rise to features of 8p23.1 DS including developmental delay, dysmorphism, macrocephaly and otitis media, but not congenital heart disease (CHD). This MRO spans 776 kb (chr8:10,167,881-10,943,836 hg19) and contains SOX7 and seven of the other 32 core 8p23.1 DS genes. In centromeric 8p23.1, microduplications including GATA4 can give rise to non-syndromic CHD but the clinical significance of two smaller centromeric microduplications without GATA4 was uncertain due to severe neurological profiles not usually found in 8p23.1 DS. The clinical significance of three further 8p23.1 microduplications was uncertain due to additional genetic factors without which the probands might not have come to medical attention. Variable expressivity was indicated by the almost entirely unaffected parents in all five families and the mildly affected sibling in one. Intronic interruptions of six genes by microduplication breakpoint intervals had no apparent additional clinical consequences. Our results suggest that 8p23.1 DS is an oligogenetic condition largely caused by the duplication and interactions of the SOX7 and GATA4 transcription factors.

8p23.1 duplication syndrome; common, confirmed, and novel features in six further patients.

The 8p23.1 duplication syndrome is a relatively rare genomic condition that has been confirmed with molecular cytogenetic methods in only 11 probands and five family members. Here, we describe another prenatal and five postnatal patients with de novo 8p23.1 duplications analyzed with oligonucleotide array comparative genomic hybridization (oaCGH). Of the common features, mild or moderate developmental delays and/or learning difficulties have been found in 11/12 postnatal probands, a variable degree of mild dysmorphism in 8/12 and congenital heart disease (CHD) in 4/5 prenatal and 3/12 postnatal probands. Behavioral problems, cleft lip and/or palate, macrocephaly, and seizures were confirmed as additional features among the new patients, and novel features included neonatal respiratory distress, attention deficit hyperactivity disorder (ADHD), ocular anomalies, balance problems, hypotonia, and hydrocele. The core duplication of 3.68 Mb contains 31 genes and microRNAs of which only GATA4, TNKS, SOX7, and XKR6 are likely to be dosage sensitive genes and MIR124-1 and MIR598 have been implicated in neurocognitive phenotypes. A combination of the duplication of GATA4, SOX7, and related genes may account for the variable penetrance of CHD. Two of the duplications were maternal and intrachromosomal in origin with maternal heterozygosity for the common inversion between the repeats in 8p23.1. These additional patients and the absence of the 8p23.1 duplications in published controls, indicate that the 8p23.1 duplication syndrome may now be considered a pathogenic copy number variation (pCNV) with an estimated population prevalence of 1 in 58,000.

Longstanding behavioural stability in West Africa extends to the Middle Pleistocene at Bargny, coastal Senegal.

Middle Stone Age (MSA) technologies first appear in the archaeological records of northern, eastern and southern Africa during the Middle Pleistocene epoch. The absence of MSA sites from West Africa limits evaluation of shared behaviours across the continent during the late Middle Pleistocene and the diversity of subsequent regionalized trajectories. Here we present evidence for the late Middle Pleistocene MSA occupation of the West African littoral at Bargny, Senegal, dating to 150 thousand years ago. Palaeoecological evidence suggests that Bargny was a hydrological refugium during the MSA occupation, supporting estuarine conditions during Middle Pleistocene arid phases. The stone tool technology at Bargny presents characteristics widely shared across Africa in the late Middle Pleistocene but which remain uniquely stable in West Africa to the onset of the Holocene. We explore how the persistent habitability of West African environments, including mangroves, contributes to distinctly West African trajectories of behavioural stability.

Impact of an STI Diagnosis on People Living With HIV in La Romana, Dominican Republic: A Cross-Sectional, Qualitative, Descriptive Study.

ABSTRACT: The objective of this study was to explore how receiving a sexually transmitted infection (STI) diagnosis affects subsequent STI knowledge and sexual risk behavior among key populations in La Romana, Dominican Republic (DR) who participated in a parent study 12 to 24 months before the current study. Nine participants, with a mean age of 37 years (range 20-54 years) and a female majority (89%), who were recruited from the parent study completed in-depth interviews, questionnaires assessing STI knowledge, and received STI testing. Interviews were analyzed using qualitative descriptive methodology and questionnaire data, comparing individual's responses between the parent and current studies. Participants reported safer sexual behaviors after original STI diagnosis, such as more frequent condom use. Questionnaires showed improvement in STI knowledge between the parent and current studies. Three participants had an STI reinfection. Findings warrant further exploration into more comprehensive and targeted STI treatment methods for key populations in the DR.

Timing and dynamics of Late Wolstonian Substage 'Moreton Stadial' (MIS 6) glaciation in the English West Midlands, UK.

Glaciation during the late Middle Pleistocene is widely recognized across continental northwest Europe, but its extent and palaeoenvironmental significance in the British Isles are disputed. Although glaciogenic sediments at Wolston, Warwickshire, in the English West Midlands, have been used to define the stratotype of the Wolstonian Stage, their age has been variably assigned between marine isotope stages (MIS) 12 and 6. Here we present sedimentological and stratigraphical observations from five sites across the English West Midlands whose chronology is constrained by new luminescence ages from glaciofluvial sediments, supplemented by cosmogenic 36Cl exposure dating of erratic boulders. The ages suggest that between 199 ± 5 and 147 ± 2.5 ka the British Ice Sheet advanced into the English West Midlands as far south as Moreton-in-Marsh, Gloucestershire. This advance is assigned to the Moreton Stadial of the Late Wolstonian Substage. Dating of the glaciation to this substage allows correlation of the Moreton Stadial glacial deposits in the English West Midlands with those of the Drenthe Stadial during the Late Saalian Substage across continental northwest Europe.

Transmitted deletions of medial 5p and learning difficulties; does the cadherin cluster only become penetrant when flanking genes are deleted?

The central portion of the short arm of chromosome 5 is unusual in that large, cytogenetically visible interstitial deletions segregate in families with and without phenotypic consequences. Here we present a family in which a transmitted interstitial deletion of 5p13.3 to 5p14.3 co-segregated with learning and/or behavioral difficulties in six family members. Facial dysmorphism was not striking but a father and daughter both had lacrimal fistulae. The deletion was 12.23 Mb in size (chr5:20,352,535-32,825,775) and contained fifteen known protein coding genes. Five of these (GOLPH3; MTMR12; ZFR; SUB1; and NPR3) and an ultra-conserved microRNA (hsa-miR-579) were present in an 883 kb candidate gene region in 5p13.3 that was deleted in the present family but not in previously reported overlapping benign deletions. Members of the cadherin precursor gene cluster, with brain specific expression, were deleted in both affected and benign deletion families. The candidate genes in 5p13.3 may be sufficient to account for the consistent presence or absence of phenotype in medial 5p deletions. However, we consider the possibility of position effects in which CDH6, and/or other cadherin genes, become penetrant when adjacent genes, or modifiers of gene expression, are also deleted. This could account for the absence of intellectual disability in benign deletions of the cadherin cluster, the cognitive phenotype in medial 5p deletion syndrome and the greater severity of intellectual disability in patients with cri-du-chat syndrome and deletions of 5p15 that extend into the region deleted in the present family.

Continuity of the Middle Stone Age into the Holocene.

The African Middle Stone Age (MSA, typically considered to span ca. 300-30 thousand years ago [ka]), represents our species' first and longest lasting cultural phase. Although the MSA to Later Stone Age (LSA) transition is known to have had a degree of spatial and temporal variability, recent studies have implied that in some regions, the MSA persisted well beyond 30 ka. Here we report two new sites in Senegal that date the end of the MSA to around 11 ka, the youngest yet documented MSA in Africa. This shows that this cultural phase persisted into the Holocene. These results highlight significant spatial and temporal cultural variability in the African Late Pleistocene, consistent with genomic and palaeoanthropological hypotheses that significant, long-standing inter-group cultural differences shaped the later stages of human evolution in Africa.

A de novo 4q34 interstitial deletion of at least 9.3 Mb with no discernible phenotypic effect.

Cytogenetically visible imbalances without phenotypic effect are still rare despite the extent of large-scale copy number variation in the normal population revealed by array CGH. Here we report on a phenotypically normal 30-year-old female with a de novo, cytogenetically visible, interstitial deletion of band 4q34. She was referred following three successive miscarriages, one of which was an intra-uterine death with subendocardial fibroelastosis and dilated cardiomyopathy. There was no other notable medical or family history, she was of normal intelligence and had no dysmorphic features. FISH and Array CGH with a customized 1 Mb BAC array showed that the deletion is a minimum of 9.3 and a maximum of 10.7 Mb in size, between approximately 173 Mb in 4q34.1 and approximately 182 Mb in 4q34.3. The deletion contains only 23 known coding genes giving a low average gene density of approximately 2 genes/Mb. This case further illustrates that (1) sizeable imbalances can be associated with apparent phenotypic normality, (2) gene density is a better guide to possible phenotypic consequences than aberration size, and (3) it is not always safe to assume that de novo imbalances will be causal.

Long-term sediment decline causes ongoing shrinkage of the Mekong megadelta, Vietnam.

Since the 1990s the Mekong River delta has suffered a large decline in sediment supply causing coastal erosion, following catchment disturbance through hydropower dam construction and sand extraction. However, our new geological reconstruction of 2500-years of delta shoreline changes show that serious coastal erosion actually started much earlier. Data shows the sandy coast bounding river mouths accreted consistently at a rate of +2 to +4 km2/year. In contrast, we identified a variable accretion rate of the muddy deltaic protrusion at Camau; it was < +1 km2/year before 1400 years ago but increased drastically around 600 years ago, forming the entire Camau Peninsula. This high level of mud supply had sharply declined by the early 20th century after a vast canal network was built on the delta. Since then the Peninsula has been eroding, promoted by the conjunction of mud sequestration in the delta plain driven by expansion of rice cultivation, and hysteresis of long-term muddy sedimentation that left the protrusion exposed to wave erosion. Natural mitigation would require substantial increases in sediment supply well above the pre-1990s levels.

Mid-Devensian climate and landscape in England: new data from Finningley, South Yorkshire.

While there is extensive evidence for the Late Devensian, less is known about Early and Middle Devensian (approx. 110-30 ka) climates and environments in the UK. The Greenland ice-core record suggests the UK should have endured multiple changes, but the terrestrial palaeo-record lacks sufficient detail for confirmation from sites in the British Isles. Data from deposits at Finningley, South Yorkshire, can help redress this. A channel with organic silts, dated 40 314-39 552 cal a BP, contained plant macrofossil and insect remains showing tundra with dwarf-shrub heath and bare ground. Soil moisture conditions varied from free draining to riparian, with ponds and wetter vegetated areas. The climate was probably low arctic with snow cover during the winter. Mutual climatic range (MCR), based on Coleoptera, shows the mean monthly winter temperatures of -22 to -2°C and summer ones of 8-14°C. Periglacial structures within the basal gravel deposits and beyond the glacial limits indicate cold-climate conditions, including permafrost. A compilation of MCR reconstructions for other Middle Devensian English sites shows that marine isotope stage 3-between 59 and 28 ka-experienced substantial variation in climate consistent with the Greenland ice-core record. The exact correlation is hampered by temporal resolution, but the Finningley site stadial at approximately 40 ka may correlate with the one of the Greenland stadials 7-11.

16p11.2-p12.2 duplication syndrome; a genomic condition differentiated from euchromatic variation of 16p11.2.

Chromosome 16 contains multiple copy number variations (CNVs) that predispose to genomic disorders. Here, we differentiate pathogenic duplications of 16p11.2-p12.2 from microscopically similar euchromatic variants of 16p11.2. Patient 1 was a girl of 18 with autism, moderate intellectual disability, behavioural difficulties, dysmorphic features and a 7.71-Mb (megabase pair) duplication (16:21 521 005-29 233 146). Patient 2 had a 7.81-Mb duplication (16:21 382 561-29 191 527), speech delay and obsessional behaviour as a boy and, as an adult, short stature, macrocephaly and mild dysmorphism. The duplications contain 65 coding genes of which Polo-like kinase 1 (PLK1) has the highest likelihood of being haploinsufficient and, by implication, a triplosensitive gene. An additional 1.11-Mb CNV of 10q11.21 in Patient 1 was a possible modifier containing the G-protein-regulated inducer of neurite growth 2 (GPRIN2) gene. In contrast, the euchromatic variants in Patients 3 and 4 were amplifications from a 945-kb region containing non-functional immunoglobulin heavy chain (IGHV), hect domain pseudogene (HERC2P4) and TP53-inducible target gene 3 (TP53TG3) loci in proximal 16p11.2 (16:31 953 353-32 898 635). Paralogous pyrosequencing gave a total copy number of 3-8 in controls and 8 to >10 in Patients 3 and 4. The 16p11.2-p12.2 duplication syndrome is a recurrent genomic disorder with a variable phenotype including developmental delay, dysmorphic features, mild to severe intellectual disability, autism, obsessive or stereotyped behaviour, short stature and anomalies of the hands and fingers. It is important to differentiate pathogenic 16p11.2-p12.2 duplications from harmless, microscopically similar euchromatic variants of proximal 16p11.2, especially at prenatal diagnosis.