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PRDM9 plays a key role in specifying meiotic recombination hotspot locations in humans. To examine the effects of both the 13-bp sequence motif (cis-regulator) and trans-regulator PRDM9 on crossover frequencies and distribution, we studied Hotspot DA. This hotspot had the motif at its centre, and a single nucleotide polymorphism (SNP) that disrupts the motif. The crossover frequency showed Hotspot DA to be a regular hotspot with an average crossover rate (~8 X10-4) among hotspots assayed on autosomes. Our results show that, comparing the rates and distributions of sperm crossover events between donors heterozygous for the disrupting SNP showed that there was a huge asymmetry between the two alleles, with the derived, motif-disrupting allele completely suppressing hotspot activity. Intensive biased gene conversion, both in to crossovers and noncrossovers, has been found at Hotspot DA. Biased gene conversion that influences crossover and non-crossover hotspot activity correlates with PRDM9 allele A. In Hotspot DA, the lifetime of the hotspot mostly depends on the cis-regulatory disrupting SNP, and on the trans-regulatory factor PRDM9. Overall, our observation showed that Hotspot DA is the only evidence for human crossover hotspot regulation by a very strong cisregulatory disrupting SNP.

Objective: Stepped-care has been suggested in the management of patients with problematic hypoglycemia and impaired awareness of hypoglycemia (IAH), initially with psychoeducational programs based on blood glucose awareness training, progressing to diabetes technology in those with persisting need. We examined the clinical effectiveness of stepped-care starting with HypoAware and adding continuous glucose monitoring (CGM) as needed, versus immediate CGM in type 1 diabetes patients with problematic hypoglycemia despite previous structured education in insulin adjustment. Research Design and Methods: A randomized controlled trial (N = 52, mean age 53, 56% females). The stepped-care group attended HypoAware. If a severe hypoglycemic event (SHE) had occurred or IAH was still present after 6 months, CGM was initiated. The control group started immediate CGM. Primary endpoint was the number of participants with self-reported SHE. Secondary outcomes, evaluated at 6 and 12 months, were glycated hemoglobin (HbA1c), the number of participants with IAH time below range (TBR; <54 mg/dL), and patient-reported outcomes (PROs). Results: At 6 months, the number of patients reporting SHE had decreased significantly more in the CGM group: -39% (P < 0.05). HbA1c decreased more in the CGM group (-0.47 percentage-points, P < 0.05). IAH was restored in 31% of patients in both groups. TBR (<54 mg/dL) was lower in the CGM group (-2.4 percentage-points, P < 0.05). In the stepped-care group, 93% started CGM/intermittently scanned CGM. At 12 months, the number of patients reporting SHE was still higher in the stepped-care group. No differences were found in PROs. Conclusions: Immediate start of CGM is more effective than a hypoglycemia-focused reeducation program in reducing SHE risk and attaining glycemic targets in individuals with problematic hypoglycemia and IAH despite previous education in insulin dose adjustment. Trial registration: Netherlands Trial Register, NL64474.029.18. [ABSTRACT FROM AUTHOR]

1. Through this case study, participants will find that patient care advocacy, even at the very end of life, can yield collaborative and creative approaches in providing patient-centered care. 2. This case study demonstrates that concurrent hospice care may be the most appropriate model of end-of-life care for patients with terminal anorexia. A case study from a Midwestern academic medical center shows that advocating for concurrent hospice care for a patient with terminal anorexia may help mitigate the challenges and controversy in defining and diagnosing the condition while still acknowledging a patient's poor prognosis and patient and family need for supportive services. Severe Enduring Anorexia Nervosa (SE-AN), also known as "terminal anorexia," is a rare, but life-threatening progression of restrictive and other eating-disordered behaviors. Recently clinical characteristics of SE-AN have been proposed with ongoing debate about the appropriateness and utilization of such guidelines. Those who work in palliative care and end of life are tasked with attenuating the suffering of patients with life-limiting or terminal illnesses. That challenge is heightened when the patient's condition is uncommon or when the care team has little experience with a particular clinical context. Given the relative youth of those with SE-AN coupled with the supposition of a terminal psychiatric disorder can bring discomfort to those charged with caring for patients with SE-AN. A case report from a Midwestern academic medical center about a 20-year-old woman with SE-AN provides an example of end-of-life care for this vulnerable population that is not guideline-focused, but patient-centered. When she enrolled in hospice, the hospice organization offered to cover ongoing treatment while simultaneously providing supportive care services to her and her family. She ultimately died on hospice, but the concurrent care model offers a pathway that acknowledges the care team's concern about poor prognosis while supporting any pivot toward life-prolonging treatment and simultaneously supporting the patient and family through this difficult scenario. Models of Palliative Care Delivery / Advocacy / Policy/ Regulations [ABSTRACT FROM AUTHOR]

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Meiotic recombination ensures the correct segregation of homologous chromosomes during gamete formation and contributes to DNA diversity through both large-scale reciprocal crossovers and very localised gene conversion events, also known as noncrossovers. Considerable progress has been made in understanding factors such as PRDM9 and SNP variants that influence the initiation of recombination at human hotspots but very little is known about factors acting downstream. To address this, we simultaneously analysed both types of recombinant molecule in sperm DNA at six highly active hotspots, and looked for disparity in the transmission of allelic variants indicative of any cis-acting influences. At two of the hotspots we identified a novel form of biased transmission that was exclusive to the noncrossover class of recombinant, and which presumably arises through differences between crossovers and noncrossovers in heteroduplex formation and biased mismatch repair. This form of biased gene conversion is not predicted to influence hotspot activity as previously noted for SNPs that affect recombination initiation, but does constitute a powerful and previously undetected source of recombination-driven meiotic drive that by extrapolation may affect thousands of recombination hotspots throughout the human genome. Intriguingly, at both of the hotspots described here, this drive favours strong (G/C) over weak (A/T) base pairs as might be predicted from the well-established correlations between high GC content and recombination activity in mammalian genomes. [ABSTRACT FROM AUTHOR]

PRDM9 has recently been identified as a likely trans regulator of meiotic recombination hot spots in humans and mice. PRDM9 contains a zinc finger array that, in humans, can recognize a short sequence motif associated with hot spots, with binding to this motif possibly triggering hot-spot activity via chromatin remodeling. We now report that human genetic variation at the PRDM9 locus has a strong effect on sperm hot-spot activity, even at hot spots lacking the sequence motif. Subtle changes within the zinc finger array can create hot-spot nonactivating or enhancing variants and can even trigger the appearance of a new hot spot, suggesting that PRDM9 is a major global regulator of hot spots in humans. Variation at the PRDM9 locus also influences aspects of genome instability-specifically, a megabase-scale rearrangement underlying two genomic disorders as well as minisatellite instability-implicating PRDM9 as a risk factor for some pathological genome rearrangements. [ABSTRACT FROM AUTHOR]

Creatine or one of 15 amino acids were mixed with minced pork before broiling at 200°C. Total mutagenic activity and reversed-phase HPLC-separated mutagenicity profiles were determined for the crust and pan residue of all samples and also in the aerosol fraction of the smoke formed during cooking of the creatine-fortified samples. Addition of 5% (w/w) creatine increased the total mutagenicity 4-fold without changing the mutagenicity profde of either crust, pan residue or aerosol. Amino acid addition (1% w/w) increased the total mutagenicity between 1.5 (lysine) and 43 times (threonine). In most cases the mutagenicity profiles of crust and pan residues were changed by amino acid addition. Dry-heated mixtures of amino acids and creatine were all mutagenic with a 250-fold range between the amino acids. The production of known food mutagens in these mixtures was analyzed by LC-MS of HPLC-fractionated mutagenic peaks. Serine, threonine, phenylalanine, alanine, leucine and tyrosine were all shown to give rise to one of the known food mutagens 2-amino-3,8-dimethylimidazo[4,5-]quinoxaline (MeIQx), 2-amino-1-methyl- 6-phenylimidazo[4,5-]pyridine (PhIP) or 2-amino-trimethylimidazopyridine (TMIP). Lyophilized and subsequently fried meat patties and a heated powder of lyophilized meat juice were both mutagenic, with mutagenicity profiles similar to the regular meat crust, showing that water is not a prerequisite for mutagen formation in meat. MeIQx, 2-amino-3,4,8-trimethylimidazo[4,5-]quinoxaline (4,8-di-MeIQx) and PhIP were shown, by LC-MS, to be present in the dry-heated meat juice. It is concluded that creatine and free amino acids are the main reactants of the mutagenforming reactions that occur during frying of meat. Creatine is probably a necessary part of all of these reactions; what specific compounds are formed in each case therefore depends upon the levels in the meat of certain free amino acids and their interactions with other, as yet unknown, compounds in the meat. [ABSTRACT FROM PUBLISHER]

The article presents the highlights of the conference "Crossroads--Archaeology Before and After #excavationinprogress" held by the Swedish Archaeological Society together with Liv Nilsson Stutz at Linnaeus University, Campus Växjö, on October 8-10, 2020. The conference was attended by archaeologists to discuss the problems of sexual harassment in archaeology exposed during the #metoo outcry in 2017. Robin Nelson from Santa Clara University in California delivered an online lecture.