The role of booster vaccination and ongoing viral evolution in seasonal circulation of SARS-CoV-2.

Periodic resurgences of COVID-19 in the coming years can be expected, while public health interventions may be able to reduce their intensity. We used a transmission model to assess how the use of booster doses and non-pharmaceutical interventions (NPIs) amid ongoing pathogen evolution might influence future transmission waves. We find that incidence is likely to increase as NPIs relax, with a second seasonally driven surge expected in autumn 2022. However, booster doses can greatly reduce the intensity of both waves and reduce cumulative deaths by 20% between 7 January 2022 and 7 January 2023. Reintroducing NPIs during the autumn as incidence begins to increase again could also be impactful. Combining boosters and NPIs results in a 30% decrease in cumulative deaths, with potential for greater impacts if variant-adapted boosters are used. Reintroducing these NPIs in autumn 2022 as transmission rates increase provides similar benefits to sustaining NPIs indefinitely (307 000 deaths with indefinite NPIs and boosters compared with 304 000 deaths with transient NPIs and boosters). If novel variants with increased transmissibility or immune escape emerge, deaths will be higher, but vaccination and NPIs are expected to remain effective tools to decrease both cumulative and peak health system burden, providing proportionally similar relative impacts.

Siglec expression on the surface of human, bull and ram sperm.

Sialic acid (Sia) is a major constituent of both the sperm glycocalyx and female reproductive mucosal surface and is involved in regulating sperm migration, uterotubal reservoir formation and oocyte binding. Siglecs (sialic acid-binding immunoglobulin - like lectins) commonly found on immune cells, bind to Sia in a linkage- and sugar-specific manner and often mediate cell-to-cell interactions and signalling. Proteomic and transcriptomic analysis of human and bovine sperm have listed Siglecs, but to date, their presence and/or localisation on sperm has not been studied. Therefore, the aim of this study was to characterise the presence of Siglecs on the surface of bovine, human and ovine sperm using both immunostaining and Western blotting. Siglec 1, 2, 5, 6, 10 and 14 were identified and displayed both species- and regional-specific expression on sperm. Almost universal expression across Siglecs and species was evident in the sperm neck and midpiece region while variable expression among Siglecs, similar among species, was detected in the head and tail regions of the sperm. The possible role for these proteins on sperm is discussed.

Glycoproteins and glycosidases of the cervix during the periestrous period in cattle.

The cervix and its secretions undergo biochemical and physical changes under the differential influences of estrogen and progesterone. These include changes in the glycoprotein profile of the endocervix and its secretions. A comprehensive survey of such changes in cervical epithelium and cervical secretions was performed on bovine samples throughout the periestrous period. Cervical tissue samples and swabs were collected from synchronized beef heifers that were slaughtered 1) 12 h after controlled intravaginal progesterone-releasing device (CIDR) removal, 2) 24 h after CIDR removal, 3) at the onset of estrus, 4) 12 h after the onset of estrus, 5) 48 h after the onset of estrus, and 6) 7 d after the onset of estrus. Histological staining with hematoxylin and eosin, periodic acid Schiff, Alcian blue, and high-iron diamine was carried out to map overall patterns of stored glycoproteins and tissue structure. Biotinylated lectins were also used to detect the presence and distribution of a range of saccharide structures. The activities of ß-galactosidase, α-L-fucosidase, ß-N-acetyl-hexosaminidase, and sialidase were measured in cervical swabs using specific substrates. The epithelial layer of the cervix exhibited dynamic changes in cellular hypertrophy and amounts of stored glycoprotein. The greatest content of neutral and acidic mucins was observed 48 h after onset of estrus (P < 0.05). Sialylated mucins predominated at the bases of cervical folds, whereas sulfated mucins were more abundant (P < 0.05) at their apices. The stained area of core mucin glycans changed (P < 0.05) in association with follicular versus luteal phases, whereas terminal glycans changed (P < 0.05) mainly at the time of estrus and shortly thereafter. The greatest activity of ß-galactosidase and sialidase was observed 12 h after onset of estrus, whereas ß-hexosaminidase and α-fucosidase peaked at the luteal time point (P < 0.05). Taken together, we suggest that the well-known changes in the endocervix and its secretions that are associated with the physiological modulation of sperm transport and function of the cervical barrier are, in part, driven by glycosylation changes.

Free radical reactions on soluble supports from ring-opening metathesis.

[reaction: see text]. Free radical reactions were performed on soluble ring-opening metathesis (ROM) polymers. These polymers have high substrate loading, short reaction times, and the benefit of a facile purification. All reactions on these supports were obtained in good yields as white crystalline-like materials readily separated from tin byproducts.

Defective bone formation and anabolic response to exogenous estrogen in mice with targeted disruption of endothelial nitric oxide synthase.

Nitric oxide (NO) is a pleiotropic signaling molecule that is produced by bone cells constitutively and in response to diverse stimuli such as proinflammatory cytokines, mechanical strain, and sex hormones. Endothelial nitric oxide synthase (eNOS) is the predominant NOS isoform expressed in bone, but its physiological role in regulating bone metabolism remains unclear. Here we studied various aspects of bone metabolism in female mice with targeted disruption of the eNOS gene. Mice with eNOS deficiency (eNOS KO) had reduced bone mineral density, and cortical thinning when compared with WT controls and histomorphometric analysis of bone revealed profound abnormalities of bone formation, with reduced osteoblast numbers, surfaces and mineral apposition rate. Studies in vitro showed that osteoblasts derived from eNOS KO mice had reduced rates of growth when compared with WT and were less well differentiated as reflected by lower levels of alkaline phosphatase activity. Mice with eNOS deficiency lost bone normally following ovariectomy but exhibited a significantly blunted anabolic response to high dose exogenous estrogen. We conclude that the eNOS pathway plays an essential role in regulating bone mass and bone turnover by modulating osteoblast function.

Association of attending physician specialty with the cesarean delivery rate in the same patient population.

BACKGROUND AND OBJECTIVES: In the context of a dramatic increase in US cesarean delivery rates over the past 30 years and explicit national goals to decrease the cesarean rate, previous retrospective studies have shown that pregnant women cared for by family physicians may be less likely to undergo cesarean delivery, compared with patients cared for by obstetricians. METHODS: We conducted a retrospective chart review of 3,560 deliveries from the family practice service of a community-based family practice residency from 1986-1995, focusing primarily on cesarean delivery rates during two periods of time. During period 1 (n = 1,063), all attending were private practice obstetricians. After a transition period, all births were attended by family medicine faculty (period 2, n = 1,346). RESULTS: The total cesarean delivery rate declined from 16.7% in period 1 to 11.1% in period 2. Repeat cesareans declined from 8.5% to 2.9%. CONCLUSIONS: In this community-based residency, a change in the specialty of the attending physician was associated with a 34% decline in the cesarean delivery rate. The observed decline in the cesarean rate could not be accounted for by any change in patient demographics or secular trends in cesarean delivery rates.

Centrality preferences in choices among similar options.

Three explanations were explored for the finding that people prefer the middle option rather than the extremes when choosing from an array of similar options. In Study 1, 68% chose the middle item from a set of three highlighters and three surveys, whereas 32% chose an item from either end, p < .0001. In Study 2, 71% selected the middle chair from a row of three chairs that were either all empty, or had a backpack occupying either one of the two end chairs, p < .0001. These results support a minimal mental effort principle rather than a preference for symmetry rule. In Study 3, 54.2% recalled more graphic items from the center poster of a 3-poster collage, whereas 31.3% and 14.5% recalled more items from the left and right posters, respectively, p < .004. These findings lend additional support to a focus of attention explanation.

The effects of in vivo pulmonary oxygenation on lung liquid production in near-term fetal sheep.

Lung liquid (LL) is secreted into the fetal lung lumen, but it must be rapidly absorbed at birth to allow air breathing. In vitro studies have implicated oxygen as a possible factor causing the switch from secretion to absorption of lung liquid at birth. We developed a technique of oxygenating the fetal lung using liquid ventilation with haemoglobin (Hb) solutions in chronically catheterized fetal lambs (129-140 days gestation; term, 147 days). In some experiments 2,3-diphosphoglycerate (DPG) was added to increase oxygen delivery. LL secretion rate (Jv) was measured using an indicator dilution method. Eighteen fetuses were divided into four groups and ventilated with liquid under the following conditions: (i) Hb with oxygen, (ii) Hb without oxygen, (iii) Hb with DPG and oxygen and (iv) Hb and DPG without oxygen. There was a significant rise (2.6 mmHg, P < 0.02) in fetal arterial Po2 in group iii, but in none of the other groups. In the first 3 h of liquid ventilation there was no difference in Jv between the groups. In group i, during hours 4-6 of liquid ventilation, there was a significant rise in secretion rate from 2.25 +/- 0.88 to 3.74 +/- 0.85 ml h-1 kg-1 (P < 0.001). In group iii, when comparing Jv in the first 3 h of liquid ventilation with that in the following 3 h period of liquid ventilation, a strong trend towards reduction in secretion was observed, falling from 3.03 +/- 0.65 to 0.74 +/- 0.92 ml h-1 kg-1 (three of the four experiments showed a significant decrease in Jv in hours 4-6). These experiments indicate that oxygen delivered to the fetus using liquid ventilation with haemoglobin solutions leads to increased LL secretion when oxygen delivery is small, and suggest there is a decrease in secretion with greater oxygen delivery to the lung.

pH-dependent spectroscopic changes associated with the hydroquinone of FMN in flavodoxins.

Photoreduction with a 5-deazaflavin as the catalyst was used to convert flavodoxins from Desulfovibrio vulgaris, Megasphaera elsdenii, Anabaena PCC 7119, and Azotobacter vinelandii to their hydroquinone forms. The optical spectra of the fully reduced flavodoxins were found to vary with pH in the pH range of 5.0-8.5. The changes correspond to apparent pKa values of 6.5 and 5.8 for flavodoxins from D. vulgaris and M. elsdenii, respectively, values that are similar to the apparent pKa values reported earlier from the effects of pH on the redox potential for the semiquinone-hydroquinone couples of these two proteins (7 and 5.8, respectively). The changes in the spectra resemble those occurring with the free two-electron-reduced flavin for which the pKa is 6.7, but they are red-shifted compared with those of the free flavin. The optical changes occurring with flavodoxins from D. vulgaris and A. vinelandii flavodoxins are larger than those of free reduced FMN. The absorbance of the free and bound flavin increases in the region of 370-390 nm (Delta epsilon = 1-1.8 mM-1 cm-1) with increases of pH. Qualitatively similar pH-dependent changes occur when FMN in D. vulgaris flavodoxin is replaced by iso-FMN, and in the following mutants of D. vulgaris flavodoxin in which the residues mutated are close to the isoalloxazine of the bound flavin: D95A, D95E, D95A/D127A, W60A, Y98S, W60M/Y98W, S96R, and G61A. The 13C NMR spectrum of reduced D. vulgaris [2,4a-13C2]FMN flavodoxin shows two peaks. The peak due to C(4a) is unaffected by pH, but the peak due to C(2) broadens with decreasing pH; the apparent pKa for the change is 6.2. It is concluded that a decrease in pH induces a change in the electronic structure of the reduced flavin due to a change in the ionization state of the flavin, a change in the polarization of the flavin environment, a change in the hydrogen-bonding network around the flavin, and/or possibly a change in the bend along the N(5)-N(10) axis of the flavin. A change in the ionization state of the flavin is the simplest explanation, with the site of protonation differing from that of free FMNH-. The pH effect is unlikely to result from protonation of D95 or D127, the negatively charged amino acids closest to the flavin of D. vulgaris flavodoxin, because the optical changes observed with alanine mutants at these positions are similar to those occurring with the wild-type protein.

An allylstannane reagent on non-cross-linked polystyrene support.

[reaction: see text] A new allylstannane reagent on non-cross-linked polystyrene was developed for the first time. This support differs markedly from standard cross-linked polymers because it is completely soluble in organic solvents; moreover, the reactions can be conveniently monitored directly by standard 1H NMR methods. The allylstannane underwent a free radical reaction with an alkyl halide to form a new allyl appendage. Tin byproducts can be easily recovered from cold methanol as white crystalline solids.

Inhibition of human type IV collagenase by a highly conserved peptide sequence derived from its prosegment.

The proenzyme fragment of the 72 kDa type IV collagenase contains a conserved amino acid sequence, MRKPRCGN(V)PDV, that is shared with other members of the matrix metalloproteinase family, such as interstitial collagenase and stromelysin. This sequence is lost upon the autocatalytic removal of the 80-84 amino acids from the amino terminus of these proenzymes following enzyme activation. The loss of this profragment converts the latent proenzyme species into a stable active enzyme species. In the present study, we demonstrate that this conserved prosegment sequence is an inhibitor of these enzymes and plays a critical role in maintenance of the latent state of the matrix metalloproteinases. Peptides containing the conserved sequence, MRKPRCGNPDV, were capable of inhibiting activated enzyme. Free cysteine was also an effective inhibitor, whereas reduced glutathione was a less effective inhibitor. Oxidized glutathione was not inhibitory. The 72 kDa type IV collagenase holoproenzyme preparations did not contain a free cysteinyl side chain that reacted with the sulfhydryl substitution reagent 5,5'-dithiobis(2-nitrobenzoic acid) (Ellman's reagent). However, addition of ethylenediaminetetraacetic acid to the reaction mixture to generate the apoenzyme form resulted in the detection of titrable sulfhydryl side chains. Based on these data, we postulate that in the latent enzyme state the conserved profragment sequence interacts with the metal atom at the active site through a sulfhydryl-metal atom coordination that is further stabilized by the amino acyl residues surrounding the essential 73Cys residue. Disturbance of this interaction results in enzyme activation.(ABSTRACT TRUNCATED AT 250 WORDS)

Radiographic evaluation for nasal dysfunction: computed tomography versus plain films.

Sixty-two patients, presenting to the Nasal Dysfunction Clinic at the University of California, San Diego, were radiographically examined with plain sinus x-rays and computed tomographic (CT) scans. The x-rays were evaluated independently, and the reported findings were compared. In maxillary sinuses the CT and plain film observations corresponded poorly with a concordance of 77%. There was a tendency to overread the plain films. In the ethmoid sinuses the lack of concordance between CT scans and plain films was 76%, and a tendency to underread the plain films was noted. In the lower nasal compartment the correspondence between CT and plain film readings was 57%, with a notable tendency to overread the plain films. In the olfactory recess, the CT/plain film concordance was 66%. At our institution, a sinus CT series costs $400; a conventional sinus series costs $102. The CT radiation dose is 5.2 to 6.5 cGY compared with 1.4 cGY for plain films. We conclude that plain films are unreliable and no longer routinely indicated for the evaluation of nasal and paranasal sinus disease. When radiographic evaluation is indicated a limited CT series provides superior information. Exceptions may include children and some cases of sinus disease isolated to a single sinus.

Survey research and the silent majority.

A survey conducted at the New York University Dental Center demonstrated that significant differences exist between patients who are ready participants in research efforts and those who require the more persistent attention of the researcher. In addition, patients who were questioned while in treatment emphasized different reasons for selecting a dental school for treatment than did those patients who were interviewed prior to beginning treatment. The importance of collecting data from a truly random sample of patients is stressed and elaborated with reference to the marketing implications of the results. Strategies for patient recruitment and retention require knowledge that is complete and does not suffer from systematic absences in the data base. Careful data collection methods are described and advocated.