Insight into infrageneric circumscription through complete chloroplast genome sequences of two Trillium species.
Genomic events including gene loss, duplication, pseudogenization and rearrangement in plant genomes are valuable sources for exploring and understanding the process of evolution in angiosperms. The family Melanthiaceae is distributed in temperate regions of the Northern Hemisphere and divided into five tribes (Heloniadeae, Chionographideae, Xerophylleae, Melanthieae and Parideae) based on the molecular phylogenetic analyses. At present, complete chloroplast genomes of the Melanthiaceae have been reported from three species. In the previous genomic study of Liliales, atrnI-CAU gene duplication event was reported fromParis verticillata, a member of Parideae. To clarify the significant genomic events of the tribe Parideae, we analysed the complete chloroplast genome sequences of twoTrilliumspecies representing two subgenera:TrilliumandPhyllantherum InTrillium tschonoskii(subgenusTrillium), the circular double-stranded cpDNA sequence of 156 852 bp consists of two inverted repeat (IR) regions of 26 501 bp each, a large single-copy (LSC) region of 83 981 bp and a small single-copy (SSC) region of 19 869 bp. The chloroplast genome sequence ofT. maculatum(subgenusPhyllantherum) is 157 359 bp in length, consisting of two IRs (25 535 bp), one SSC (19 949 bp) and one LSC (86 340 bp), and is longer than that ofT. tschonoskii The results showed that the cpDNAs of Parideae are highly conserved across genome structure, gene order and contents. However, the chloroplast genome ofT. maculatumcontained a 3.4-kb inverted sequence betweenndhCandrbcLin the LSC region, and it was a unique feature for subgeneraPhyllantherum In addition, we found three different types of gene duplication in the intergenic spacer betweenrpl23andycf2containingtrnI-CAU, which were in agreement with the circumscription of subgenera and sections in Parideae excludingT. govanianum These genomic features provide informative molecular markers for identifying the infrageneric taxa ofTrilliumand improve our understanding of the evolution patterns of Parideae in Melanthiaceae.


Hearing loss induced by viscous fluids in the middle ear.
Dextran solutions of low viscosity (7.5 centipoise) and high viscosity (2.2 poise) were instilled in turn into the middle ears of guinea pigs, using an open bulla preparation. The degree of conductive hearing loss induced was assessed by measurement of the cochlear microphonic. Both solutions produced a comparable degree of hearing loss which was frequency dependent, ranging from 30 dB at 500 Hz to almost zero at 4000 Hz. The results indicate that the degree of conductive hearing loss produced by a serous effusion in otitis media is due solely to an effect on compliance in the middle ear and is independent of the viscosity of the effusion.


Preparation of low density lipoprotein-9-methoxy-ellipticin complex and its cytotoxic effect against L1210 and P 388 leukemic cells in vitro.
Previous studies have suggested that low density lipoprotein (LDL) may be used as a drug targeting carrier for chemotherapeutic agents to neoplastic cells. In this study the cytotoxic agent 9-methoxy-ellipticin (MeOE) was incorporated into dimirystoyl phosphatidylcholine, cholesteryl oleate stabilized microemulsion and the latter fused with human LDL. Both agarose electrophoresis migration and the electron microscopic shape of the drug-LDL complexes were similar to those of native LDL. The in vitro cytotoxic tests on L1210 and P388 leukemic cells demonstrated that the complex was able to kill cells and was more effective than the free drug. This cytotoxic activity of the drug-LDL complex depends on the LDL high affinity receptor: the native LDL reduces the killing power. In contrast, methylated LDL, which does not bind to the LDL receptor, has no effect on it. On the other hand, heparin, which prevents binding on the cell surface receptors, partially reduced the cytotoxic activity of the drug-lipoprotein complex. These results suggest that it is possible to incorporate lipophilic cytotoxic drugs into LDL, using a technique of fusion with the microemulsion which contains the drug. This technique allows us to obtain a drug-LDL complex which is able to kill cells via the LDL receptor pathway.


Differential development of ectopic testes based on their location in rats.
In order to investigate the effect of location on the development of ectopic testes, the relationship between the degree of degenerative change in ectopic testes and their original position was examined in rat models of cryptorchidism. Unilateral ectopic testes were created by excising the future scrotal skin on either the right or left side in newborn rats. At 60 days of age, the position of the testes was examined, the testicular weight and seminiferous tubular diameter (STD) were measured, and spermatogenesis was evaluated using the Johnsen score. All the rats showed maldescended testes on the operated side, with the testes descending into the superficial inguinal pouch, the perineum or the transverse contralateral scrotum. The testicular weight, STD and Johnsen score were all significantly lower for the superficial inguinal testes than for either the perineal or contralateral scrotal testes. These findings suggest that the degree of testicular degeneration depends on the position of the ectopic testes; the higher the testicular location, the greater the histological changes.


Radiation protection for your hands.
A prospective clinical trial was performed to assess the suitability of a new type of sterilisable, user-friendly radiation protection glove. In a preliminary trial, we showed that the dominant hand of the primary operating orthopaedic surgeon receives the highest dose of radiation. During a 4-month period, 98 procedures were done requiring the use of an image intensifier. The doses of radiation to the dominant hand of the operating surgeon were reduced to less than the doses of radiation to the non-dominant hand. The glove was sterilisable, user-friendly and accepted by the majority of surgeons. It offers greater than 90% attenuation of X-rays and is superior to all other scatter gloves on the market.


Anxiety-like behaviors produced by acute fluoxetine administration in male Fischer 344 rats are prevented by prior exercise.
Although selective 5-HT reuptake inhibitors (SSRIs) can reduce anxiety after chronic treatment, acute SSRI administration is associated with an increase in anxiety consistent with an acute increase in 5-HT neurotransmission. Exercise is anxiolytic in humans, and wheel running prevents anxiety-like behavioral consequences of uncontrollable stress in rats, but the effects of exercise on acute fluoxetine-induced anxiety-like behaviors are unknown. The current studies tested the hypothesis that acute administration of the SSRI fluoxetine would produce behaviors in rats resembling those produced by uncontrollable stress and that these behaviors would be blocked by prior wheel running. Adult, male Fisher 344 rats administered moderate (10 mg/kg) or high (20 mg/kg) doses of fluoxetine demonstrated exaggerated shock-elicited freezing and an interference with shuttle box escape compared to rats given either saline or low-dose fluoxetine (2.5 mg/kg). Fluoxetine-induced behaviors were similar to, but smaller in magnitude than, those produced by uncontrollable stress and were blocked by pretreatment with the 5-HT(2C) receptor antagonist SB 242084 (1 mg/kg). Rats allowed access to running wheels for 6 weeks were protected against the anxiety-like behaviors produced by a single injection of fluoxetine (10 mg/kg). Behavioral effects of acute fluoxetine administration resemble those produced by uncontrollable stress. Results are consistent with the idea that exercise can produce resistance against the anxiogenic effects of acute increases in 5-HT and suggest that acute behavioral effects of antidepressants can depend on history of physical activity.


The Callender modification of the Macintosh laryngoscope blade reduces the risk of tooth-blade contact in children.
Dental injury is well recognized as a potential complication of laryngoscopy and tracheal intubation. The flange of the Macintosh blade may contact teeth during laryngoscopy causing damage. The Callander modification of the Macintosh blade (Callander blade) with a shortened heel at the proximal end has been shown to increase the blade-tooth distance and reduce contact rates in adults. This study was designed to evaluate the effectiveness of the Callander blade on reducing dental contact in children. One hundred children, aged 4-14 years, scheduled for general anesthesia requiring endotracheal intubation were studied prospectively. The children were preoperatively evaluated for Mallampati score and dental defects, looseness, and avulsions. Following induction of anesthesia, laryngoscopy was performed twice on each child in succession, once with a standard Macintosh blade and once with a Callander blade of the same size in a random order. The blade-tooth distance and contact rate were compared between the two blades. With the Callander blade, the blade-tooth distance was greater than with the Macintosh (1.78 +/- 1.77 vs 0.28 +/- 0.76 mm, P = 0.001). The frequency of direct contact was less with the Callander blade than it was with the Macintosh blade (33% vs 86%, respectively, P = 0.008). However, difficult laryngoscopy rate did not differ between the blades. Tracheal intubation was successful in all children and there was no dental injury. Our findings suggest that the Callander blade decreases the risk for dental injury and provides tracheal intubating conditions in children with normal airways similar to those obtained with a traditional Macintosh blade.


Jack of one trade, master of none: host choice by Drosophila magnaquinaria.
Host selection by phytophagous insects is generally thought to be based on chemical or nutritional characteristics of the host. This is especially true for monophagous insects. However, many other factors may influence host choice. The present study examines host selection by Drosophila magnaquinaria, whose sole host is the yellow skunk cabbage, Lysichitum americanum. Utilization of skunk cabbage was tested relative to a set of alternative hosts. In the pre-alighting stage of host selection, skunk cabbage was found to be less attractive than tomato, cucumber, and commercial mushrooms. In pairwise oviposition tests, there were no differences among hosts. There were no differences in larval survivorship among skunk cabbage, tomato, cucumber, or Ramaria, and larvae developed into pupae earlier on tomato than on skunk cabbage. These results indicate that this monophagy is not based on characteristics of the host. We suggest that habitat selection is the more important factor in determining the association between D. magnaquinaria and skunk cabbage.


Simulation Training in Obstetrics and Gynaecology Residency Programs in Canada.
The integration of simulation into residency programs has been slower in obstetrics and gynaecology than in other surgical specialties. The goal of this study was to evaluate the current use of simulation in obstetrics and gynaecology residency programs in Canada. A 19-question survey was developed and distributed to all 16 active and accredited obstetrics and gynaecology residency programs in Canada. The survey was sent to program directors initially, but on occasion was redirected to other faculty members involved in resident education or to senior residents. Survey responses were collected over an 18-month period. Twelve programs responded to the survey (11 complete responses). Eleven programs (92%) reported introducing an obstetrics and gynaecology simulation curriculum into their residency education. All respondents (100%) had access to a simulation centre. Simulation was used to teach various obstetrical and gynaecological skills using different simulation modalities. Barriers to simulation integration were primarily the costs of equipment and space and the need to ensure dedicated time for residents and educators. The majority of programs indicated that it was a priority for them to enhance their simulation curriculum and transition to competency-based resident assessment. Simulation training has increased in obstetrics and gynaecology residency programs. The development of formal simulation curricula for use in obstetrics and gynaecology resident education is in early development. A standardized national simulation curriculum would help facilitate the integration of simulation into obstetrics and gynaecology resident education and aid in the shift to competency-based resident assessment. Obstetrics and gynaecology residency programs need national collaboration (between centres and specialties) to develop a standardized simulation curriculum for use in obstetrics and gynaecology residency programs in Canada.


Impact of hypoalbuminemia on in-hospital mortality in patients with takotsubo syndrome: A multicenter registry of the Tokyo Cardiovascular Care Unit Network.
Hypoalbuminemia is common in critically ill patients and is associated with poor outcomes. However, the relationship between serum albumin levels and clinical outcomes in patients with takotsubo syndrome remains unclear. We examined the impact of hypoalbuminemia on in-hospital mortality in patients with takotsubo syndrome. Using the multicenter registry of the Tokyo Cardiovascular Care Unit Network between January 2017 and December 2020, we identified 631 eligible patients with takotsubo syndrome (median age, 78 years; male proportion, 22 %) and documented serum albumin levels at admission, which were used to allocate patients to hypoalbuminemia (serum albumin <3.5 g/dL) or normal albumin (serum albumin ≥3.5 g/dL) groups. Patient characteristics and in-hospital mortality were compared between the groups. Hypoalbuminemia was detected in 200 (32 %) patients at admission. The hypoalbuminemia group was older and had a higher proportion of men and preceding physical triggers than the normal albumin group. In-hospital all-cause mortality was greater in the hypoalbuminemia group than in the normal albumin group (9.5 % vs. 1.9 %, p < 0.001). Both cardiac (3.0 % vs. 0.5 %, p = 0.015) and non-cardiac (6.5 % vs. 1.4 %, p = 0.002) mortality was greater in the hypoalbuminemia group. In multivariable logistic regression analysis, hypoalbuminemia was independently associated with increased in-hospital mortality, even after adjusting for confounders, including age, sex, and triggering events (odds ratio, 3.23; 95 % confidence interval, 1.31-7.95; p = 0.011). In patients with takotsubo syndrome, hypoalbuminemia is a common comorbidity and is associated with a substantial risk of in-hospital death. Close monitoring and comprehensive critical care are required in these patients.


Risk factors for maternal complications following uterine rupture: a 12-year single-center experience.
To determine maternal outcomes and risk factors for composite maternal morbidity following uterine rupture during pregnancy. A retrospective cohort study including all women diagnosed with uterine rupture during pregnancy, between 2011 and 2023, at a single-center. Patients with partial uterine rupture or dehiscence were excluded. We compared women who had composite maternal morbidity following uterine rupture to those without. Composite maternal morbidity was defined as any of the following: maternal death; hysterectomy; severe postpartum hemorrhage; disseminated intravascular coagulation; injury to adjacent organs; admission to the intensive care unit; or the need for relaparotomy. The primary outcome was risk factors associated with composite maternal morbidity following uterine rupture. The secondary outcome was the incidence of maternal and neonatal complications following uterine rupture. During the study period, 147,037 women delivered. Of them, 120 were diagnosed with uterine rupture. Among these, 44 (36.7%) had composite maternal morbidity. There were no cases of maternal death and two cases of neonatal death (1.7%); packed cell transfusion was the major contributor to maternal morbidity [occurring in 36 patients (30%)]. Patients with composite maternal morbidity, compared to those without, were characterized by: increased maternal age (34.7 vs. 32.8 years, p = 0.03); lower gestational age at delivery (35 + 5 vs. 38 + 1 weeks, p = 0.01); a higher rate of unscarred uteri (22.7% vs. 2.6%, p < 0.01); and rupture occurring outside the lower uterine segment (52.3% vs. 10.5%, p < 0.01). Uterine rupture entails increased risk for several adverse maternal outcomes, though possibly more favorable than previously described. Numerous risk factors for composite maternal morbidity following rupture exist and should be carefully assessed in these patients.


Reconstruction of chronic patellar tendon rupture using graft from contralateral patella graft together with reinforcement from flexor tendons. Case report.
Chronic patellar tendon rupture is a rare disabling injury that is technically difficult to repair. The true prevalence of this injury is unknown. Delayed reconstruction of chronic patellar tendon rupture has yielded suboptimal clinical and functional results. Many different surgical methods for reconstruction of chronic patellar tendon injury have been reported. In this report, we present a case with chronic patellar tendon injury that was addressed using a technique that had not previously been described in the literature, through combining procedures that had been described separately. The reconstruction method presented in this article has the advantages of being easy and reproducible, without a requirement of allografts.


Neuropsychological profiles of persons with mental retardation and dementia.
This study examined the use of neuropsychological tests to assist in the differential diagnosis of dementia among persons with mental retardation. The author compared performances of persons with mental retardation and dementia (n = 10) to persons with mental retardation without dementia (n = 12). Participants were matched by IQ (mild or moderate mental retardation), age, presence of Down syndrome, and gender. In addition, all participants in the dementia group had corroborative medical tests (i.e., imaging, EEG, or high tau low AB42 protein testing) consistent with diagnosis of dementia. Test performance was compared on measures of attention and executive functions, language, memory and learning, and a dementia screening. Results from MANOVAs and nonparametric tests revealed significantly lower performance for persons with mental retardation and dementia in all areas assessed. Cut-off scores were also developed for the sample in order to maximize sensitivity and specificity for the test battery. Despite the small sample size, these findings suggest that there are significant measurable differences in several neurocognitive domains between the two groups.


Use of Adaptive Focused Acoustics™ ultrasound in controlling liposome formation.
Many techniques for producing large unilamellar vesicles (LUVs) or small unilamellar vesicles (SUVs) have drawbacks, including exposure of sensitive biological materials to harsh organic solvents or high temperatures. Here we describe the use of controlled focused ultrasound, Adaptive Focused Acoustics™ (AFA), to make LUV or SUV at low temperature without organic solvents and at a consistent, chosen size. We studied the effects of peak incident power (PIP), cycles per burst (CPB), duty factor (DF), temperature, and lipid composition (natural or synthetic), on liposome size distribution. We found that an increase in PIP, DF, CPB, or temperature decreased liposome size. When processed under the same conditions as the natural lipid composition [Phospholipon 90 G], the synthetic lipid composition [HSPC, DSPE-PEG-2000, Chol] generally produced larger liposomes, although extending processing time reduced liposomes to similar size. In combination with AFA, these trends can help pinpoint parameter values that achieve a desired liposome size distribution.


The presence of Helicobacter pylori in the larynx pathologies.
The well-known relation of Helicobacter pylori to the MALT-lymphoma and gastric carcinoma suggested a possible presence in the laryngeal tissues of patients with squamous cell carcinoma of the larynx by using Polymerase Chain Reaction (PCR) investigations, and PCR results of benign laryngeal pathologies were compared. Polymerase Chain Reaction investigations were carried out in biopsy samples of 21 patients with squamous cell carcinoma of the larynx and of 19 patients with benign laryngeal pathologies like vocal polyp and nodules. The PCR results of 17 out of the 21 samples (80.9%) of the patients with laryngeal squamous cell carcinoma were positive for H. pylori. Moreover, any genomic material of H. pylori was not found in the PCR results of the 19 patients with benign laryngeal pathology. It was also determined that the presence of the H. pylori in the patients with laryngeal squamous cell carcinoma was statistically significant (p=0.0001). In the patients with laryngeal squamous cell carcinoma, the comparison of the H. pylori presence within the normal and tumoral tissues revealed that 16 normal tissue samples (76.19%) were positive, while 9 of the tumoral tissue samples (42.85%) were positive. The ratio of bacterial presence in both the normal and tumor tissue samples was 38.09% (8 patients). The rates of presence revealed a statistically significant difference between the normal and tumoral tissue samples (p=0.039). The presence of the genomic material of H. pylori within the laryngeal tissue of patients with squamous cell carcinoma of the larynx is a proof of the colonization of the bacterium in that tissue. While this may suggest a possible relation of the bacterium to the development of laryngeal squamous cell carcinoma, no conclusion is possible to be drawn about the mechanism of the process.


Interleukin-1ß and interleukin-1 receptor accessory protein gene polymorphisms are associated with persistent hepatitis B virus infection.
The reasons for persistent HBV infection are unknown, but they are probably related to host immune factors. IL-1ß plays significant roles in inflammation and immune defense via IL-1RAcP. We investigated whether genetic polymorphisms of IL-1ß and IL-1RAcP genes are associated with persistent HBV infection and the presence of HCC. We enrolled a total of 292 patients with chronic HBV infection (111 with chronic hepatitis, 95 with liver cirrhosis and 86 with HCC) and 107 healthy individuals who recovered from HBV infection. We assessed 28 SNPs in IL- 1ß and IL-1RAcP genes by using Illumina's Sentrix array matrix chip. IL-1ß-2023 C allele, IL-1RAcP -8261 T allele and -8183 A allele were significantly associated with persistent HBV infection (OR=1.63, p=0.03, OR=0.64, p<0.01 and OR=0.20, p=0.01, respectively). IL- 1ß 289 C allele was marginally associated with an increased risk for the presence of HCC (OR=1.55, p=0.04). On the haplotype analysis, IL-1ß-2023C/-581C/2893C haplotype and IL-1RAcP -8261T/-8183A haplotype were associated with persistent HBV infection. There was no significant association between the haplotypes of IL-1ß/IL-1RAcP and the presence of HCC. The genetic polymorphisms of IL-1ß-2023 C allele, IL- 1RAcP -8261 T allele and -8183 A allele are probable host factors for persistent HBV infection.


Fostering interpersonal trust on social media: physicians' perspectives and experiences.
The problem of developing and sustaining mutual trust is one of the main barriers to knowledge sharing on social media platforms such as blogs, wikis, micro-blogs and social networking websites. While many studies argue that mutual trust is necessary for online communication and knowledge sharing, few have actually explored and demonstrated how physicians can establish and sustain trusted relationships on social media. To identify approaches through which physicians establish interpersonal trust on social media. Twenty-four physicians, who were active users of social media, were interviewed using a semi-structured approach between 2013 and 2014. Snowball sampling was employed for participant recruitment. The data were analysed using a thematic analysis approach. Physicians trust their peers on social media in a slightly different way than in face-to-face communication. The study found that the majority of participants established trust on social media mainly through previous personal interaction, authenticity and relevancy of voice, professional standing, consistency of communication, peer recommendation, and non-anonymous and moderated sites. Healthcare professionals need to approach social media carefully when using it for knowledge sharing, networking and developing trusted relations with like-minded peers.


[The baseline characteristics of patients with type 2 diabetes initiating insulin detemir : the Chinese cohort from the SOLVE(TM) study].
To characterize the baseline status of Chinese diabetic patients based on data derived from Chinese cohort from SOLVE(TM) study. Patients with type 2 diabetes initiating basal insulin detemir at the decision of the physician were eligible for the study. Data on demographics, medical history, glycemic profile and treatment regimen at baseline were collected by physicians. A total of 3272 patients [female 42%, male 58%, mean age (56.2 ± 10.8) years] were included in the study. Their BMI was (25.3 ± 3.3) kg/m(2). The duration of diabetes was 4.0 (0.1 - 27.0) years, and the duration of treatment with oral antidiabetic drugs (OADs) was 3.0 (0.0 - 20.2) years. The proportions of subjects with diabetic macro- and micro-vascular complications were 15.8% (515 cases) and 27.1% (866 cases), respectively. The hemoglobin A1c (HbA1c) at baseline was (8.33 ± 1.70)%, and the fasting blood glucose (FPG) was (9.5 ± 2.6) mmol/L. A large proportion of patients with type 2 diabetes remain in poor glycemic control, and the prevalence of diabetic complications is high, which requires optimal therapeutic strategy for the patients with suboptimal glycemic control.


Effects of gonadotropin-releasing hormone agonist and clomiphene citrate on estrogen/progesterone-induced hyperprolactinemia in monkeys.
The effects of follicular phase clomiphene citrate (CC) and two regimens of leuprolide acetate on estrogen-progesterone-induced hyperprolactinemia in nonhuman primates were studied. All groups received estradiol (E2) benzoate (12.5 micrograms intramuscularly on cycle days 2 to 33) and progesterone (P) (silastic implant for cycle days 14 to 33). A gonadotropin-releasing hormone agonist (GnRH-a) (Lupron 0.5 mg daily, TAP Pharmaceuticals, Chicago, IL) was administered from cycle day 2 to 14 in group II and from day 20 of the previous cycle until cycle day 14 in group III. Oral CC was given on cycle days 3 through 7 in group IV. No significant differences of mean E2 and P concentrations were noted between groups. Neither GnRH-a nor CC had an overall effect on E2/P-induced hyperprolactinemia. However, for the 5-day interval at the onset of the P treatment there was a significant increase in prolactin (PRL) secretion for group II (130.4 +/- 30.6) versus group I (53.9 +/- 3.3), group III (64.4 +/- 11.1), and group IV (68.8 +/- 14.3). This suggests that leuprolide may exert a delayed stimulatory effect on PRL secretion, or that complete suppression of the putative paracrine regulation of PRL stimulation may require more than 13 days of GnRH-a administration.


The influence of socio-economic status and multimorbidity patterns on healthcare costs: a six-year follow-up under a universal healthcare system.
Multimorbidity has been linked to elevated healthcare utilization and previous studies have found that socioeconomic status is an important factor associated with multimorbidity. Nonetheless, little is known regarding the impact of multimorbidity and socioeconomic status on healthcare costs and whether inequities in healthcare exist between socioeconomic classes within a universal healthcare system. This longitudinal study employed the claims database of the National Health Insurance of Taiwan (959 990 enrolees), adopting medication-based Rx-defined morbidity groups (Rx-MG) as a measurement of multimorbidity. Mixed linear models were used to estimate the effects of multimorbidity and socioeconomic characteristics on annual healthcare costs between 2005 and 2010. The distribution of Rx-MGs and total costs presented statistically significant differences among gender, age groups, occupation, and income class (p < .001). Nearly 80% of the enrolees were classified as multimorbid and low income earners presented the highest prevalence of multimorbidity. After controlling for age and gender, increases in the number of Rx-MG assignments were associated with higher total healthcare costs. After controlling for the effects of Rx-MG assignment and demographic characteristics, physicians, paramedical personnel, and public servant were found to generate higher total costs than typical employees/self-employed enrolees, while low-income earners generated lower costs. High income levels were also found to be associated with lower total costs. It was also revealed that occupation and multimorbidity have a moderating effect on healthcare cost. Increases in the prevalence of multimorbidity are associated with higher health care costs. This study determined that instances of multimorbidity varied according to socioeconomic class; likewise there were inequities in healthcare utilization among individuals of various occupations and income levels, even when demographic characteristics and multimorbidity were controlled for. This highlights the importance of socioeconomic status with regard to healthcare utilization. These results indicate that socioeconomic factors should not be discounted when discussing the utilization of healthcare by patients with multimorbidity.


REM sleep modulation by perifornical orexinergic inputs to the pedunculo-pontine tegmental neurons in rats.
Rapid eye movement sleep (REMS) is regulated by the interaction of the REM-ON and REM-OFF neurons located in the pedunculo-pontine-tegmentum (PPT) and the locus coeruleus (LC), respectively. Many other brain areas, particularly those controlling non-REMS (NREMS) and waking, modulate REMS by modulating these REMS-related neurons. Perifornical (PeF) orexin (Ox)-ergic neurons are reported to increase waking and reduce NREMS as well as REMS; dysfunction of the PeF neurons are related to REMS loss-associated disorders. Hence, we were interested in understanding the neural mechanism of PeF-induced REMS modulation. As a first step we have recently reported that PeF Ox-ergic neurons modulate REMS by influencing the LC neurons (site for REM-OFF neurons). Thereafter, in this in vivo study we have explored the role of PeF inputs on the PPT neurons (site for REM-ON neurons) for the regulation of REMS. Chronic male rats were surgically prepared with implanted bilateral cannulae in PeF and PPT and electrodes for recording sleep-waking patterns. After post-surgical recovery sleep-waking-REMS were recorded when bilateral PeF neurons were stimulated by glutamate and simultaneously bilateral PPT neurons were infused with either saline or orexin receptor1 (OX1R) antagonist. It was observed that PeF stimulation increased waking and decreased NREMS as well as REMS, which were prevented by OX1R antagonist into the PPT. We conclude that the PeF stimulation-induced reduction in REMS was likely to be due to inhibition of REM-ON neurons in the PPT. As waking and NREMS are inversely related, subject to confirmation, the reduction in NREMS could be due to increased waking or vice versa. Based on our findings from this and earlier studies we have proposed a model showing connections between PeF- and PPT-neurons for REMS regulation.


Elevated retina-specific expression of the small heat shock protein, alphaA-crystallin, is associated with photoreceptor protection in experimental uveitis.
During the early phase of experimental autoimmune uveitis (EAU), before macrophages infiltrate the retina and uvea, photoreceptor mitochondrial oxidative stress, nitration of photoreceptor mitochondrial proteins, and release of cytochrome c have been observed. However, no apoptosis has been detected during this phase. In this study, alphaA-crystallin upregulation in the retina and its antiapoptotic protective role were evaluated in early EAU. Gene microarrays were first used to identify upregulated genes in retinas with early EAU. Among highly upregulated crystallins, alphaA was confirmed by real-time polymerase chain reaction and Western blot, and the site of upregulation was localized by immunohistochemistry. The association of alphaA-crystallin to nitrated cytochrome c and interaction with a procaspase-3 subunit was assayed. Photoreceptor apoptosis in alphaA knockout mice was compared with that in wild-type animals with EAU, by using the terminal transferase dUTP nick-end labeling assay and polymerase chain reaction. In early EAU, alphaA-crystallin was increased 33-fold, and the site of increase was localized to the photoreceptor inner segments. This crystallin suppressed apoptosis by associating with the nitrated cytochrome c and p24. The association with nitrated cytochrome c, in particular, appeared to be restricted to nitrated cytochrome c, and thus, no association of non-nitrated cytochrome c was detected. The knockout mice showed signs of EAU development early and showed apoptosis in the retina; no such changes were seen in the wild-type control animals. alphaA-Crystallin is highly upregulated in the retina during early EAU. This upregulation is localized primarily in the photoreceptor inner segments, the site of mitochondrial oxidative stress. Further, in early EAU, the photoreceptors preferentially use alphaA-crystallin to suppress mitochondrial oxidative stress-mediated apoptosis.


Cardiomyocytes generating spontaneous Ca2+-transients as tools for precise estimation of sarcoplasmic reticulum Ca2+ transport.
Spontaneous Ca2+-transient (wave) generation in isolated cardiomyocytes is well established phenomenon which poses a lot of questions about myocardial excitability. Current studies of spontaneous Ca2+-activity in cardiac cells mainly relate to the kinetic characteristics, classification and simulation of Ca2+-events through ryanodine receptor (RyR) activity modeling. Here, for the first time we pay attention to the Ca2+-transients having stationary kinetics for correct estimation of the sarcoplasmic reticulum Ca2+ transport. In cardiomyocytes generating such type of Ca2+-transients, the averaged intracellular calcium ([Ca2+]in) fluorescence practically does not change in time. Stationary Ca2+-transients are observed in different animal models (Wistar, SHR, ground squirrels) revealing a common cardiomyocyte phenomenon. They somewhat depend on external Ca2+ ([Ca2+]ex) because the [Ca2+]ex lowering to 1 μM in the presence of EGTA disrupts Ca2+-wave propagation. At the same time, spontaneous Ca2+-transients do not associated with the forward or reverse mode of Na+/Ca2+ exchanger (NCX), but partially modulated by the L-type Ca2+-channels. Among the sarcoplasmic reticulum targets, RyR and SERCA are crucial for Ca2+-wave generation and sustained self-oscillation activity. Analysis of the spontaneous wave kinetics reveals that both slopes of the rising wave front and the wave front decline are gradually changed during propagation, which well correlates with the RyR and SERCA activity, respectively. On the contrary, in the electrical field-stimulated myocytes, both slope factors are sharply changed corresponding to 'all-or-nothing' rule, which is fundamental principle for action potential in cardiomyocytes. Furthermore, stimulation of single cardiomyocyte using local electrode appears the deterioration in the [Ca2+]in utilization from the cytosol, which limits the time of observation during the protocol. Obtained data suggest that stationary spontaneous Ca2+-transients occurring without actual myocellular excitation represent useful and precise tools for estimation of the sarcoplasmic reticulum Ca2+-transport.


Chordoma of the Head and Neck: A Review.
Chordoma is a rare malignant bone tumor that can arise anywhere along the central neural axis and many involve head and neck sites, most commonly the skull base. The relative rarity of these tumors, combined with the complex anatomy of the head and neck, pose diagnostic challenges to pathologists. This article describes the pertinent clinical, pathologic, and molecular features of chordomas and describes how these features can be used to aid in formulating a differential diagnosis. Emphasis is placed on key diagnostic pitfalls and the importance of incorporating immunohistochemical information into the diagnosis.


Antiproliferative properties of flavone acetic acid (NSC 347512) (LM 975), a new anticancer agent.
The antiproliferative activity of flavone acetic acid (LM 975) was investigated on human adenocarcinoma cell lines (HCC-P2998, HCC-M1544, HCC-M1410, HT 29, LoVo), on a murine colon adenocarcinoma cell line (Colon 26), on murine pancreatic adenocarcinoma cells growing in primary culture (Pan 03) and on human normal fibroblasts (N1). No cytotoxic effects were found against human normal fibroblasts. LM 975 was active against murine adenocarcinoma Pan 03 and Colon 26, known to be sensitive in vivo too and, to variable extents, on human adenocarcinoma cell lines. LM 975 in vitro cytotoxic potency was relatively low. The high concentrations (1.0-1.4 mM) required to obtain a cytotoxic effect are, however, pharmacologically reasonable since they are comparable with drug plasma levels in mice or in patients treated with tolerable doses. After a relatively short LM 975 treatment (2 h) DNA, RNA and protein synthesis were inhibited in different proportions. In more sensitive cells LM 975 appeared to inhibit RNA synthesis more than DNA and protein synthesis. Inhibition of macromolecule synthesis after 2 h exposure was completely reversed in 24 h recovery. After 2 h treatment no detectable DNA breakage was found by the alkaline elution method, thus corroborating the idea that this compound does not act by causing DNA damage.


Complete resection of a huge hypervascular inflammatory myofibroblastic tumor in right hemithorax after embolization.
Inflammatory myofibroblastic tumor (IMT) is a rare and mostly benign tumor that has the possibility of malignant change. Radiological findings revealed a huge mass that filled most of the right hemithorax of a 17-monthold female infant. Tumor extirpation was stopped due to massive bleeding and limited exposure of the tumor. Embolization was conducted to obstruct the arteries feeding the mass. Complete resection was performed. Histopathologic examination led to the diagnosis of IMT. Postoperative recovery was uneventful. Hypervascularity of IMT should be considered. Preoperative embolization can be effective to reduce intraoperative blood loss and facilitate the surgical procedure.


Small-incision lenticule extraction in a patient with congenital nystagmus.
We report a case of a 23-year-old woman with congenital nystagmus who had small-incision lenticule extraction (SMILE) procedure to correct refractive errors. The manifest refraction was -5.50 -1.75 × 180 in the right eye, -5.0 -2.50 × 180 in the left eye, and the patient presented with horizontal pendular nystagmus with an amplitude range of 5 to 10 degrees. Uneventful simultaneous bilateral small-incision lenticule extraction was performed. Six months postoperatively, the uncorrected distance visual acuity was 20/18 with -0.25, -0.25 × 80 in the right eye, and 20/20 with +0.25 -0.5 × 50 in the left eye. The case suggests that small-incision lenticule extraction can be an effective alternative for correcting myopic astigmatism in patients with nystagmus.


Gout gone awry: The importance of proper diagnosis.
Gout is the best-known type of arthritis with a prevalence of 1%-3% in the western world (Therapeutic Advances in Musculoskeletal Disease, 6, 2014 and 131; Journal of Advanced Research, 8, 2017 and 495). Although it is well understood, there is growing evidence of the misdiagnosis of gout from other forms of arthritis. These errors lead to delay in accurate diagnosis (Journal of Advanced Research, 8, 2017 and 495).


Prevalence and influencing factors of depressive and anxiety symptoms among hospital-based healthcare workers during the surge period of the COVID-19 pandemic in the Chinese mainland: a multicenter cross-sectional study.
From November 2022 to February 2023, the Chinese mainland experienced a surge in COVID-19 infection and hospitalization, and the hospital-based healthcare workers (HCWs) might suffer serious psychological crisis during this period. This study aims to assess the depressive and anxiety symptoms among HCWs during the surge of COVID-19 pandemic and to provide possible reference on protecting mental health of HCWs in future infectious disease outbreaks. A multicenter cross-sectional study was carried out among hospital-based HCWs in the Chinese mainland from 5 January to 9 February 2023. The PHQ-9 (nine-item Patient Health Questionnaire) and GAD-7 (seven-item Generalized Anxiety Disorder Questionnaire) were used to measure depressive and anxiety symptoms. Ordinal logistic regression analysis was performed to identify influencing factors. A total of 6522 hospital-based HCWs in the Chinse mainland were included in this survey. The prevalence of depressive symptoms among the HCWs was 70.75%, and anxiety symptoms was 47.87%. The HCWs who perceived higher risk of COVID-19 infection and those who had higher work intensity were more likely to experience depressive and anxiety symptoms. Additionally, higher levels of mindfulness, resilience and perceived social support were negatively associated with depressive and anxiety symptoms. This study revealed that a high proportion of HCWs in the Chinese mainland suffered from mental health disturbances during the surge of the COVID-19 pandemic. Resilience, mindfulness and perceived social support are important protective factors of HCWs' mental health. Tailored interventions, such as mindfulness practice, should be implemented to alleviate psychological symptoms of HCWs during the COVID-19 pandemic or other similar events in the future.


Ankle joint mobilization reduces axonotmesis-induced neuropathic pain and glial activation in the spinal cord and enhances nerve regeneration in rats.
An important issue in physical rehabilitation is how to protect from or to reduce the effects of peripheral nerve injury. In the present study, we examined whether ankle joint mobilization (AJM) would reduce neuropathic pain and enhance motor functional recovery after nerve injury. In the axonotmesis model, AJM during 15 sessions every other day was conducted in rats. Mechanical and thermal hyperalgesia and motor performance deficit were measured for 5 weeks. After 5 weeks, we performed morphological analysis and quantified the immunoreactivity for CD11b/c and glial fibrillary acidic protein (GFAP), markers of glial activation, in the lumbar spinal cord. Mechanical and thermal hyperalgesia and motor performance deficit were found in the Crush+Anesthesia (Anes) group (P<0.001), which was significantly decreased after AJM (P<0.001). In the morphological analysis, the Crush+Anes group presented reduced myelin sheath thickness (P<0.05), but the AJM group presented enhanced myelin sheath thickness (P<0.05). Peripheral nerve injury increased the immunoreactivity for CD11b/c and GFAP in the spinal cord (P<0.05), and AJM markedly reduced CD11b/c and GFAP immunoreactivity (P<0.01). These results show that AJM in rats produces an antihyperalgesic effect and peripheral nerve regeneration through the inhibition of glial activation in the dorsal horn of the spinal cord. These findings suggest new approaches for physical rehabilitation to protect from or reduce the effects of nerve injury.


Biogas slurry topdressing as replacement of chemical fertilizers reduces leaf senescence of maize by up-regulating tolerance mechanisms.
Worldwide physiological research has aimed to decelerate the aging of crop leaves by optimizing fertilization measures to improve crop or biomass yield. Solid organic fertilizers can be combined with chemical fertilizers to delay the aging of crop leaves. Biogas slurry is a liquid organic fertilizer produced by the anaerobic fermentation of livestock and poultry manure and other resources, and it can partially replace chemical fertilizers in field application via drip irrigation systems. However, the impact of biogas slurry topdressing on leaf aging remains unclear. This study investigated treatments with no topdressing (control, CK) and five topdressing patterns of biogas slurry replacing chemical fertilizer (nitrogen) at 100%, 75%, 50%, 25%, and 0% (100%BS, 75%BS, 50%BS, 25%BS, CF). The effects of different proportions of biogas slurry on leaf senescence rate, photosynthetic pigments, osmotic adjustment substances, antioxidant defense enzymes, and nitrogen metabolism related enzyme activities of maize were analyzed. Subsequently, the mechanisms of biogas slurry topdressing on the leaf senescence rate of maize were explored. The results showed that the mean decreasing rate of relative green leaf area (Vm) treated with biogas slurry decreased by 3.7%-17.1% and the duration of leaf area duration (LAD) increased by 3.7%-17.1% compared with the results for CK. The maximum senescence rate of 100%BS was delayed by 4.4 and 5.6 d compared to the results for CF and CK, respectively. During the senescence of maize leaves, the use of biogas slurry topdressing increased the content of chlorophyll, decreased the water loss and the accumulation rate of malondialdehyde and proline in leaves, and increased the activities of catalase, peroxidase, and superoxide dismutase in the later growth and development periods of maize. In addition, biogas slurry topdressing improved the nitrogen transport efficiency of the leaves and ensured continuous and efficient ammonium assimilation. Furthermore, there was a strong correlation between leaf senescence and the investigated physiological indices. Cluster analysis showed that the 100%BS treatment exhibited the most prominent effect on leaf senescence. Biogas slurry topdressing as a substitute for chemical fertilizer can be potentially used as an anti-aging regulation measure for crops to decrease the damage induced by senescence.


Circadian clock and output genes are rhythmically expressed in extratesticular ducts and accessory organs of mice.
Circadian clocks regulate multiple rhythms in mammalian tissues. In most organs core clock gene expression is oscillatory, with negative components Per and Cry peaking in antiphase to Bmal1. A notable exception is the testis, where clock genes seem nonrhythmic. Earlier mammalian studies, however, did not examine clock expression patterns in accessory ductal tissue required for sperm maturation and transport. Previous studies in insects demonstrated control of sperm maturation in vas deferens by a local circadian system. Sperm ducts express clock genes and display circadian pH changes controlled by vacuolar-type H(+)-ATPase and carbonic anhydrase (CA-II). It is unknown whether sperm-processing rhythms are conserved beyond insects. To address this question in mice housed in a light-dark environment, we examined temporal patterns of mPer1 and Bmal1 gene expression and protein abundance in epididymis, vas deferens, seminal vesicles, and prostate. Results demonstrate variable tissue-specific patterns of expression of the two genes, with variations in levels of clock proteins and their nucleo-cytoplasmic cycling observed among examined tissues. Strikingly, mPer1 and Bmal1 mRNA and proteins oscillate in antiphase in the prostate, with similar peak-trough patterns as observed in the suprachiasmatic nuclei, the brain's central clock. Genes encoding CA and a V-ATPase subunit, which are rhythmically expressed in sperm ducts of moths, are also rhythmic in some segments of murine sperm ducts. Our data suggest that some sperm duct segments may contain peripheral circadian systems whereas others may express clock genes in a pleiotropic manner.


Promoting Diverse Youth's Career Development through Informal Science Learning: The Role of Inclusivity and Belonging.
Little research has examined the associations between perceived inclusivity within informal science learning sites, youth program belonging and perceptions of program career preparation. This study explored relations between these factors at three timepoints (T1 = start of program, T2 = 3 months and T3 = 12 months after start). Participants were a diverse sample of 209 adolescents participating in STEM youth programs within informal science learning sites situated in the United States and United Kingdom (70% females: M age = 15.27, SD age = 1.60), with 53.1% British and 64.1% non-White. Path analysis revealed that only perceptions of inclusivity for own social identity group (i.e., gender, ethnicity) at T1 were associated with T2 STEM youth program belonging. There was a significant indirect effect of T1 perceptions of inclusivity for one's own social identity groups on T3 perceptions of program career preparation via T2 program belonging. This study highlights that, over time, perceptions of inclusivity around youth's own social identity groups (i.e., gender and ethnicity/culture) are related to a sense of youth program belonging, which in turn is later associated with perceptions of program career preparation.


Synthesis and biological evaluation of imidamide analogs as selective anti-trypanosomal agents.
Human African trypanosomiasis is caused by a protozoan parasite Trypanosoma brucei majorly infecting people living in sub-Saharan Africa. Current limited available treatments suffer from drug resistance, severe adverse effects, low efficacy, and costly administrative procedures in African countries with limited medical resources. Therefore, there is always a perpetual demand for advanced drug development and invention of new strategies to combat the disease. Previous work in our lab generated a library of sulfonamide analogs as selective tubulin inhibitors, based on the structural difference between mammalian and trypanosome tubulin proteins. Further lead derivatization was performed in the current study and generated 25 potential drug candidates to improve the drug efficacy and uptake by selectively targeting the parasite's P2 membrane transporter protein with imidamide moiety. One of the newly synthesized analogs, compound 25 with a di-imidamide moiety, has shown greater potency with an IC50 of 1 nM to selectively inhibit the growth of trypanosome cells without affecting the viability of mammalian cells. Western blot analyses reveal that the compound suppressed tubulin polymerization in T. brucei cells. A detailed structure-activity relationship (SAR) was summarized that will be used to guide future lead optimization.


Postoperative pain and other sequelae of dental rehabilitations performed on children under general anesthesia.
The purpose of this study was to determine the prevalence, severity and variables influencing postoperative pain and other sequelae in children undergoing dental rehabilitation under general anesthesia. Healthy children scheduled for dental rehabilitation having treatment on only primary teeth were included in the study. General anesthesia protocol was standardized, and patients did not receive local anesthesia intraoperatively. Pain and other postoperative sequelae were recorded for 7 days postoperatively. Ninety-five percent of the 90 children had postoperative pain which was moderate in intensity and highest immediately postoperatively. Children who had extractions or were at least 4 years old and had more than 12 procedures experienced increased postoperative pain. The most common postoperative symptoms other than pain were agitation, need for analgesics, and sleepiness. Longer operative times resulted in increased postoperative sleepiness. Children whose tracheal intubations were traumatic were more likely to report sore throats. Children who were at least 4 years old required more analgesics, experienced more postoperative sleepiness, and had nausea more frequently. All postoperative problems significantly decreased by postoperative day 2 and ceased by postoperative day 4 to 5. Children undergoing dental rehabilitations under general anesthesia commonly experience postoperative symptoms such as pain, agitation, need for analgesics, and sleepiness.


Analysis of the effect of zoledronic acid on gene differences in rat jaw.
With the widespread use of bisphosphonates, there are more and more complications about bisphosphonates, bisphosphonate-related osteonecrosis of the jaw is one.In the past ten years, there have been many studies on the mechanism of bisphosphonate associated jaw necrosis. To investigate the influence and analysis of zoledronic acid on gene differences in rat jaw. Six Sprague-Dawley female rats were randomly divided into control group (n = 3) and experimental group (n = 3). The experimental group received zoledronic acid injection for 12 weeks (dose of 0.2 mg / kg, 3 times a week).Control groups were injected with normal saline for 12 weeks. All rats were subjected to left mandibular first molar extraction 12 weeks later.After 8 weeks of tooth extraction, all rats were sacrificed and the mandible was removed.RNA-seq was used to analyze differential gene changes in all mandibles. Bioinformatics analysis of differential genes. Compared with the two rat groups, there were 2,830 different genes, including 1,001 upregulated genes and 1,829 down-regulated genes. Gene Ontology analysis revealed that the upregulated genes were mainly associated with immune-related pathways. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that Hedgehog signaling pathway, Notch signaling pathway and Hippo signaling pathway were associated with upregulated genes. After the Gene Set Enrichment Analysis, the Gene Ontology analysis showed that 2559 / 6588 gene sets are upregulated in phenotype experimental group,and 342 gene sets with p <0.05. The Kyoto Encyclopedia of Genes and Genomes analysis revealed that 95 / 316 gene sets are upregulated in phenotype experimental group, and four gene sets(Notch pathway, other types of O-glycan biosynthesis, ovarian steridogenesis and Hippo pathway) with p <0.05. Changes in differential genes are mainly related to immune-related processes and pathways, and pathways related to bone metabolism. The up-regulation of some genes can promote the progress of Bisphosphonate-related osteonecrosis of the jaw.


Modulatory effects of plant phenols on human multidrug-resistance proteins 1, 4 and 5 (ABCC1, 4 and 5).
Plant flavonoids are polyphenolic compounds, commonly found in vegetables, fruits and many food sources that form a significant portion of our diet. These compounds have been shown to interact with several ATP-binding cassette transporters that are linked with anticancer and antiviral drug resistance and, as such, may be beneficial in modulating drug resistance. This study investigates the interactions of six common polyphenols; quercetin, silymarin, resveratrol, naringenin, daidzein and hesperetin with the multidrug-resistance-associated proteins, MRP1, MRP4 and MRP5. At nontoxic concentrations, several of the polyphenols were able to modulate MRP1-, MRP4- and MRP5-mediated drug resistance, though to varying extents. The polyphenols also reversed resistance to NSC251820, a compound that appears to be a good substrate for MRP4, as predicted by data-mining studies. Furthermore, most of the polyphenols showed direct inhibition of MRP1-mediated [3H]dinitrophenyl S-glutathione and MRP4-mediated [3H]cGMP transport in inside-out vesicles prepared from human erythrocytes. Also, both quercetin and silymarin were found to inhibit MRP1-, MRP4- and MRP5-mediated transport from intact cells with high affinity. They also had significant effects on the ATPase activity of MRP1 and MRP4 without having any effect on [32P]8-azidoATP[alphaP] binding to these proteins. This suggests that these flavonoids most likely interact at the transporter's substrate-binding sites. Collectively, these results suggest that dietary flavonoids such as quercetin and silymarin can modulate transport activities of MRP1, -4 and -5. Such interactions could influence bioavailability of anticancer and antiviral drugs in vivo and thus, should be considered for increasing efficacy in drug therapies.


Barriers to Bariatric Surgery: a Mixed Methods Study Investigating Obstacles Between Clinic Contact and Surgery.
Populations most affected by obesity are not reflected in the patients who undergo bariatric surgery. Gaps in the referral system have been studied, but there is a lack of literature investigating obstacles patients encounter after first contact with bariatric surgery clinics. We aim to identify patient populations at risk for attrition during bariatric surgery evaluation and determine patient reported barriers to bariatric surgical care. This study was a single institution, retrospective, mixed methods study from 2012 to 2021 comparing patients who underwent bariatric surgery to those that withdrew. Surveys were performed of patients who withdrew, collecting information on patient knowledge, expectations, and barriers. This study included 5982 patients evaluated in bariatric surgery clinic. Those who attained bariatric surgery (38.8%) were more likely to be White (81.2 vs. 75.6%, p<0.001), married (48.5 vs. 44.1%, p=0.004), and employed full time (48.2 vs. 43.8%, p=0.01). They were less likely to live in an area with low income (37.1 vs. 40.7%, p=0.01) or poverty (poverty rate 15.8 vs. 17.4, p<0.001). Of the 280 survey respondents, fear of complications, length of insurance approval process, and wait time between evaluation and surgery were the most reported barriers. Patients who undergo bariatric surgery were more likely to be White, married, employed full time, and reside in more resourced environments which is not reflective of communities most affected by obesity. The complexity of insurance coverage requirements was a major barrier to bariatric surgery and should be a focus of future healthcare reform.


Strain Identification and Quantitative Analysis in Microbial Communities.
Microbiology has long studied the ways in which subtle genetic differences between closely related microbial strains can have profound impacts on their phenotypes and those of their surrounding environments and communities. Despite the growth in high-throughput microbial community profiling, however, such strain-level differences remain challenging to detect. Once detected, few quantitative approaches have been well-validated for associating strain variants from microbial communities with phenotypes of interest, such as medication usage, treatment efficacy, host environment, or health. First, the term "strain" itself is not used consistently when defining a highly-resolved taxonomic or genomic unit from within a microbial community. Second, computational methods for identifying such strains directly from shotgun metagenomics are difficult, with several possible reference- and assembly-based approaches available, each with different sensitivity/specificity tradeoffs. Finally, statistical challenges exist in using any of the resulting strain profiles for downstream analyses, which can include strain tracking, phylogenetic analysis, or genetic association studies. We provide an in depth discussion of recently available computational tools that can be applied for this task, as well as statistical models and gaps in performing and interpreting any of these three main types of studies using strain-resolved shotgun metagenomic profiling of microbial communities.


High-Performance Doped Silver Films: Overcoming Fundamental Material Limits for Nanophotonic Applications.
The field of nanophotonics has ushered in a new paradigm of light manipulation by enabling deep subdiffraction confinement assisted by metallic nanostructures. However, a key limitation which has stunted a full development of high-performance nanophotonic devices is the typical large losses associated with the constituent metals. Although silver has long been known as the highest quality plasmonic material for visible and near infrared applications, its usage has been limited due to practical issues of continuous thin film formation, stability, adhesion, and surface roughness. Recently, a solution is proposed to the above issues by doping a proper amount of aluminum during silver deposition. In this work, the potential of doped silver for nanophotonic applications is presented by demonstrating several high-performance key nanophotonic devices. First, long-range surface plasmon polariton waveguides show propagation distances of a few centimeters. Second, hyperbolic metamaterials consisting of ultrathin Al-doped Ag films are attained having a homogeneous and low-loss response, and supporting a broad range of high-k modes. Finally, transparent conductors based on Al-doped Ag possess both a high and flat transmittance over the visible and near-IR range.


PGE2 accounts for bidirectional changes in alveolar macrophage self-renewal with aging and smoking.
Alveolar macrophages (AMs) are resident immune cells of the lung that are critical for host defense. AMs are capable of proliferative renewal, yet their numbers are known to decrease with aging and increase with cigarette smoking. The mechanism by which AM proliferation is physiologically restrained, and whether dysregulation of this brake contributes to altered AM numbers in pathologic circumstances, however, remains unknown. Mice of advanced age exhibited diminished basal AM numbers and contained elevated PGE2 levels in their bronchoalveolar lavage fluid (BALF) as compared with young mice. Exogenous PGE2 inhibited AM proliferation in an E prostanoid receptor 2 (EP2)-cyclic AMP-dependent manner. Furthermore, EP2 knockout (EP2 KO) mice exhibited elevated basal AM numbers, and their AMs resisted the ability of PGE2 and aged BALF to inhibit proliferation. In contrast, increased numbers of AMs in mice exposed to cigarette smoking were associated with reduced PGE2 levels in BALF and were further exaggerated in EP2 KO mice. Collectively, our findings demonstrate that PGE2 functions as a tunable brake on AM numbers under physiologic and pathophysiological conditions.


Specific binding of sulphated polymers to ram sperm proacrosin.
Sulphated polysaccharides and zona pellucida glycoproteins have been shown to bind non-enzymatically to proacrosin, the protein found within the acrosomal vesicle of mammalian spermatozoa. The mechanism of this interaction has been investigated using 125I-fucoidan to probe purified ram sperm proacrosin. Results show that (a) binding of 125I-fucoidan to proacrosin is inhibited only by sulphated polymers and (b) recognition is mediated by poly(sulphate) groups and is largely independent of the composition of the polymer chain. It is suggested that a similar mechanism is responsible for the interaction between proacrosin and zona pellucida glycoproteins during the early stages of fertilization in mammals and this process mediates firm binding of spermatozoa to the egg.


Spontaneous acute forearm compartment syndrome: Case report of a clinical diagnosis with limited imaging options.
Diagnostic radiology is essential for providing targeted management of different diseases. Thus, there has been a dramatic increase in the demand for medical imaging. However, acute compartment syndrome (ACS) is one of the clinical scenarios in which radiology has limited value. The authors report a nontraumatic spontaneous ACS in the forearm of a 56-year-old female. The roles of Ultrasound and MRI, if available, are also illustrated. Limited reports of spontaneous ACS are published in the literature; we hope this case adds to the limited data. Our goal in reporting this case is to improve clinical practice with favorable outcomes for the patients involved globally by alert to the onset of ACS to promote early detection and timely fasciotomy. Also, we aim to increase awareness among physicians and radiologists of the limitations of radiology in specific clinical scenarios. Finally, it may aid in illuminating a possible link between malignant hypertension, spontaneous bleeding/hematoma, and ACS.


Coincidence of vitiligo, alopecia areata, onychodystrophy, localized scleroderma and lichen planus.
The unique coincidence of five dermatological disorders, which occurred in a 39-year-old patient, is discussed. The clinical and laboratory examination did not reveal a common underlying cause. It is hoped this report will stimulate the recognition of other cases and thus aid in determining whether the coincidence of these disorders is a true association of diseases with a common underlying factor or a rare abnormality.


Women, Younger Clinicians', and Caregivers' Experiences of Burnout and Well-being During COVID-19 in a US Healthcare System.
The COVID-19 pandemic brought rapid changes to the work and personal lives of clinicians. To assess clinician burnout and well-being during the COVID-19 pandemic and guide healthcare system improvement efforts. A survey asking about clinician burnout, well-being, and work experiences. Surveys distributed to 8141 clinicians from June to August 2020 in 9 medical groups and 17 hospitals at Sutter Health, a large healthcare system in Northern California. Burnout was the primary outcome, and other indicators of well-being and work experience were also measured. Descriptive statistics and multivariate logistic regression analyses were performed. All statistical inferences were based on weighted estimates adjusting for response bias. A total of 3176 clinicians (39.0%) responded to the survey. Weighted results showed 29.2% reported burnout, and burnout was more common among women than among men (39.0% vs. 22.7%, p<0.01). In multivariate models, being a woman was associated with increased odds of reporting burnout (OR=2.19, 95% CI: 1.51-3.17) and being 55+ years old with lower odds (OR=0.54, 95% CI: 0.34-0.87). More women than men reported that childcare/caregiving was impacting work (32.9% vs. 19.0%, p<0.01). Even after controlling for age and gender, clinicians who reported childcare/caregiving responsibilities impacted their work had substantially higher odds of reporting burnout (OR=2.19, 95% CI: 1.54-3.11). Other factors associated with higher burnout included worrying about safety at work, being given additional work tasks, concern about losing one's job, and working in emergency medicine or radiology. Protective factors included believing one's concerns will be acted upon and feeling highly valued. This large survey found the pandemic disproportionally impacted women, younger clinicians, and those whose caregiving responsibilities impacted their work. These results highlight the need for a holistic and targeted strategy for improving clinician well-being that addresses the needs of women, younger clinicians, and those with caregiving responsibilities.


The effect of the anti-progestin RU 486 on early pregnancy in the long-tailed macaque (Macaca fascicularis).
The efficacy of various doses of RU 486 in terminating pregnancy before and after the luteal-placental shift (LPS) in the long-tailed macaque (Macaca fascicularis) was assessed through sonographic examination and measurements of steroid hormones and their metabolites. Intramuscular injection of 1.0, 2.5, 12.5, or 25.0 mg/kg was administered either from gestational day (GD) 15-18 (Group 1; N = 11) or GD 23-26 (Group 2; N = 9). The timing of treatment was determined by the detection of the preovulatory estrogen peak via daily urinary estrone conjugate (E1C) measurements. In Group 1, a 90.9% pregnancy loss was observed (10/11); seven animals aborted during GD 15-20, two animals indicated early embryonic death with retained gestational sacs, one animal aborted on GD 56, and one pregnancy was maintained. In Group 2, an 88.9% pregnancy loss was observed (8/9); eight animals aborted between GD 26-29, and one pregnancy was unaffected. Hormone profiles appeared to fall secondarily to the loss of trophoblast function. These results indicate: (a) RU 486 was more effective after the LPS; and (b) the primary effect of RU 486 appeared to be at the level of the products of conception.


Surgery and radioembolization of liver tumors.
Surgical resection is considered the curative treatment par excellence for patients with primary or metastatic liver tumors. However, less than 40% of them are candidates for surgery, either due to non-modifiable factors (comorbidities, age, liver dysfunction…), or to the invasion or proximity of the tumor to the main vascular requirements, the lack of a future liver remnant (FLR) adequate to maintain postoperative liver function, or criteria of tumor size and number. In these last factors, hepatic radioembolization has been shown to play a role as a presurgical tool, either by hypertrophy of the FLR or by reducing tumor size that manages to reduce tumor staging (term known as "downstaging"). To these is added a third factor, which is its ability to apply the test of time, which makes it possible to identify those patients who present progression of the disease in a short period of time (both locally and at distance), avoiding a unnecessary surgery. This paper aims to review RE as a tool to facilitate liver surgery, both through the experience of our center and the available scientific evidence.


[Inhibition of the carrageenen-induced inflammatory rat paw oedema by systemic application of rat fibrinogen and fibrinopeptides (author's transl)].
The acute inflammatory rat paw oedema induced by subplantar injection of carrageenan was significantly inhibited by intraperitoneal injection of rat fibrinogen, intraperitoneal and intracardial injection of fibrinoepetides A and B. In contrast the fibrin split products derived from plasmin digestion proved to be ineffective.


Midtrimester isolated oligohydramnios in monochorionic diamniotic multiple gestations.
To describe the natural history and perinatal outcomes of monochorionic diamniotic twins with midtrimester isolated oligohydramnios (iOligo). We performed a retrospective study of iOligo patients who were initially referred for the management of evolving twin-twin transfusion syndrome (TTTS) or selective intrauterine growth restriction (sIUGR). iOligo was defined as a maximum vertical pocket of amniotic fluid of ≤2 cm in the iOligo twin's sac and normal fluid level (>2 and <8 cm) in the co-twin's sac. "Group A" patients did not subsequently develop TTTS or sIUGR Type II (umbilical artery persistent absent or reversed end-diastolic flow), and "Group B" patients did develop TTTS or sIUGR Type II. Results are reported as median (range). Of the 828 patients with complicated monochorionic twin gestations referred for possible TTTS or sIUGR, 36 (4.3%) were initially diagnosed with iOligo. After initial consultation, two patients terminated and one was lost to follow-up, resulting in a final study population of 33. Group A had 10 patients (30.3%) and Group B had 23 patients (69.7%). In Group A, nine of the 10 were expectantly managed, resulting in a median gestational age (GA) at delivery of 34.7 (18.0-36.4) weeks, a 30-day perinatal survival of at-least-one twin of 88.9% (8/9), and dual 30-day survivors in 8/9 (88.9%). In Group B, 12 (52.2%) developed TTTS and 11 (47.8%) developed sIUGR Type II. Fifteen Group B patients had laser surgery, resulting in a median GA at delivery of 33.7 (26.4-37.1) weeks, a 30-day perinatal survival of at-least-one twin of 100% (15/15), and dual survivorship of 46.7% (7/15). Our findings show that the majority of patients with midtrimester iOligo have fetal growth restriction of the affected twin and subsequently progress to TTTS or sIUGR Type II.


Laparoscopic port site Richter's hernia after robot-assisted radical prostatectomy.
Postoperative small bowel obstruction is a rare complication. One of its less frequent causes is port site hernia. We report a case of Richter's port site hernia in a patient who underwent robot-assisted radical prostatectomy. A 73-year-old man who underwent robot-assisted radical prostatectomy noted acute abdominal pain and nausea on the 11th postoperative day. Computed tomography scans revealed dilated small bowel loops. Adhesive ileus was initially suspected, which was relieved with conservative management, including ileus tube insertion. However, his symptoms worsened. Thus, a laparotomy was performed. The camera port wound was reopened, and the repaired fascia and small intestine were found incarcerated into the peritoneal defects. These findings were consistent with Richter's hernia. Port site hernia was not detected on computed tomography scans. Patients presenting with small bowel obstruction following laparoscopic surgery should be evaluated for port site hernia, and surgical management should be considered.


Self-other resonance, its control and prosocial inclinations: Brain-behavior relationships.
Humans seem to place a positive reward value on prosocial behavior. Evidence suggests that this prosocial inclination is driven by our reflexive tendency to share in the observed sensations, emotions and behavior of others, or "self-other resonance". In this study, we examine how neural correlates of self-other resonance relate to prosocial decision-making. Subjects performed two tasks while undergoing fMRI: observation of a human hand pierced by a needle, and observation and imitation of emotional facial expressions. Outside the scanner, subjects played the Dictator Game with players of low or high income (represented by neutral-expression headshots). Subjects' offers in the Dictator Game were correlated with activity in neural systems associated with self-other resonance and anticorrelated with activity in systems implicated in the control of pain, affect, and imitation. Functional connectivity between areas involved in self-other resonance and top-down control was negatively correlated with subjects' offers. This study suggests that the interaction between self-other resonance and top-down control processes are an important component of prosocial inclinations towards others, even when biological stimuli associated with self-other resonance are limited. These findings support a view of prosocial decision-making grounded in embodied cognition.


Risk factors for oral mucositis in children undergoing chemotherapy: a matched case-control study.
Oral mucositis (OM) is the most frequent and severe complication of chemotherapy for children with cancer, yet little is known about its risk factors. The aim of this study was to determine the risk factors associated with chemotherapy-induced OM in children. A matched case-control design was used. The matching criteria were age, type of cancer and chemotherapy regimen. Patient-and treatment-related data were collected via chart review. Conditional logistic regression analyses were performed to estimate odds ratios (OR) and adjusted odds ratios (AOR) for the development of OM. Fifty-one cases and 51 controls were identified. The mean+/-SD age of the children was 7.6+/-5.2 years, with 65 (63.73%) boys. Eighty-two percent of the children had been diagnosed with haematological malignancies (n=84). The most common chemotherapy regimen was a combination of plant alkaloids and antitumor antibiotics (n=42, 41.18%). In the multivariable model, lower body weight (AOR=0.91; 95% CI=0.84-0.98; p=0.013), lower value of log nadir neutrophil count (AOR=0.33; 95% CI=0.16-0.68; p=0.0025), and higher value of peak creatinine (AOR=1.06; 95% CI=1.01-1.12; p=0.025) were significantly associated with a greater risk of OM. Our findings suggest that children who are neutropenic, those with serum creatinine elevation, and those with a low body weight prior to chemotherapy are at greater risk of developing OM.


Consequences of the radial heterogeneity of the column temperature at high mobile phase velocity.
When a high velocity stream of mobile phase percolates through a chromatographic column, the bed cannot remain isothermal. Due to the mobile phase decompression, heat is generated along the column. Longitudinal and radial temperature gradients take place along and across its bed. The various consequences of this thermal heterogeneity are calculated and their effects on the column efficiency investigated for a 0.46 cm x 25 cm stainless steel column packed with 5 microm particles. The maximum pressure drop applied was varied from 0.1 to 2 kbar. The amplitude of the longitudinal temperature gradient can be estimated on the basis of the integral heat balance equation applied to the whole column and of measurements of the eluent temperature at the column exit. Assuming that the radial gradient is parabolic and the longitudinal gradient linear, the amplitude of the radial gradient can be determined on the basis of the energy balance across the column and of direct measurements of the radial gradient at high inlet pressures. A radial temperature gradient causes a radial distribution of the eluent viscosity, hence of its local velocity. The result is that bands move faster in their center than along the wall, become warped, hence a radial concentration gradient, similar in origin to the one observed in open cylindrical tubes. Diffusion relaxes this gradient. If there is only a longitudinal temperature gradient, the column efficiency would be 30% smaller for a 2 kbar pressure drop than if there is no longitudinal temperature gradient. However, when both a longitudinal and a radial temperature gradient coexist, there is a large loss of efficiency. If the influence of the diffusive relaxation of the radial concentration gradient is neglected, the peak shape would be broad and exhibit a marked shoulder.


Confirmation of Heart Malformations in Fetuses in the First Trimester Using Three-Dimensional Histologic Autopsy.
We aimed to evaluate the usefulness of three-dimensional (3D) reconstruction of histology slides to confirm congenital heart disease (CHD) detected by first-trimester fetal cardiac ultrasonography. Conventional autopsy is hindered by the small size of the first-trimester fetal heart, and current CHD confirmation studies employ the use of highly specialized and expensive methods. An extended first-trimester ultrasound examination protocol was used to diagnose fetal heart anomalies. Medical termination of pregnancies was followed by fetal heart extraction. The specimens were sliced, and the histology slides were stained and scanned. The resulting images were processed, and volume rendering was performed using 3D reconstruction software. The volumes were analyzed by a multidisciplinary team of maternal-fetal medicine subspecialists and pathologists and compared with ultrasound examination findings. Six fetuses with heart malformations were evaluated using histologic 3D imaging: two with hypoplastic left heart syndrome, two with atrioventricular septal defects, one with an isolated ventricular septal defect, and one with transposition of the great arteries. The technique allowed us to confirm ultrasound-detected anomalies and also identified additional malformations. After pregnancy termination or loss, histologic 3D imaging can be used to confirm the presence of fetal cardiac malformations detected during first-trimester ultrasound examination. Additionally, this technique has the potential to refine the diagnosis for counseling regarding recurrence risk and retains the advantages of standard histology.


Long- and medium-term ozone effects on lung growth including a broad spectrum of exposure.
The effects of semi-annual and 3.5 yr mean ozone (O3) concentrations on children's forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) were assessed over a study period of 3.5 yrs in 2,153 schoolchildren from 15 study sites in South Western Germany and Lower Austria. Spirometric parameters were assessed twice a year, and differences between consecutive measurements divided by days were considered as a measure of lung growth. Exposure was analysed in four classes, separately for winter and summer (semi-annual mean O3 concentrations 22-30, 30-38, 38-46, 46-54 parts per billion (ppb) in summer and 4-12, 12-20, 20-28, 28-36 ppb in winter). Regression methods for repeated measurements were used, and these revealed a significantly lower FVC (FEV1) increase estimated at -19.2 (-18.5) mL x 100 days(-1) for semi-annual mean O3 exposure in summer between 46 and 54 ppb compared to exposure between 22 and 30 ppb. However, in winter, the estimated difference in FVC (FEV1) was 16.4 (10.9) mL x 100 days(-1) between the semi-annual O3 class 28-36 ppb and the 4-12 ppb class. By means of linear regression the study found that there was no association between growth rates and mean summer O3 for FVC and FEV1 over a 3.5 yr period. The authors conclude that medium-term effects on schoolchildren's lung growth are possibly present, but are in the long-term not detectable for forced vital capacity and forced expiratory volume in one second over a 3.5 yr period due to partial reversibility.


Geographical aspects of peptic ulcer surgery.
The geographic distribution of duodenal ulcer and its characteristics in rural areas of high incidence in developing countries are reviewed. The choice of surgical procedures is discussed in light of the bulky diet and nutritional problems of these countries. A vagotomy procedure is advised for duodenal ulcer and a Billroth I gastrectomy for gastric ulcers of the body of the stomach.


Association between temporal orientation and attitudes about BRCA1/2 testing among women of African descent with family histories of breast cancer.
Previous studies have identified specific attitudes (pros and cons) about BRCA testing held by women of African descent that are associated with decisions to participate in testing. These testing attitudes may be determined, in part, by temporal orientation, or how one perceives the significance of events and the consequences of their actions in terms of past, present, and future. The current study explored the relationship between temporal orientation and pros and cons of BRCA testing among 140 women of African descent with a family history suggestive of a genetic mutation predisposing to breast cancer. Participants completed measures of temporal orientation and genetic testing attitudes. Multivariate analyses indicated that future orientation was positively associated with perceived pros of testing. Additional analyses revealed significant associations between temporal orientation and specific item subsets related to the negative and positive impact of testing on family and personal control over one's health. These results support an association between temporal orientation and attitudes about BRCA testing among women of African descent with family histories of breast cancer. Findings support exploration of temporal orientation in future research on BRCA testing decisions among women of African descent and this construct's importance in developing decision aids and tailoring genetic counseling.


Withdrawal of antiseizure medications after MRI-Guided laser interstitial thermal therapy in extra-temporal lobe epilepsy.
This study investigated the success rate of antiseizure medications (ASMs) withdrawal following MRI Guided Laser Interstitial Thermal Therapy (MRg-LITT) for extra-temporal lobe epilepsy (ETLE), and identified predictors of seizure recurrence. We retrospectively assessed 27 patients who underwent MRg-LITT for ETLE. Patients' demographics, disease characteristics, and post-surgical outcomes were evaluated for their potential to predict seizure recurrence associated with ASMs withdrawal. The median period of observation post MRg-LITT was 3 years (range 18 - 96 months) and the median period to initial ASMs reduction was 0.5 years (range 1-36 months). ASMs reduction was attempted in 17 patients (63%), 5 (29%) of whom had seizure recurrence after initial reduction. Nearly all patient who relapsed regained seizure control after reinstitution of their ASMs regimen. Pre-operative seizure frequency (p = 0.002) and occurrence of acute post-operative seizures (p = 0.01) were associated with increased risk for seizure recurrence post ASMs reduction. At the end of the observation period, 11% of patients were seizure free without drugs, 52% were seizure free with drugs and 37% still experienced seizures despite ASMs. Compared with pre-operative status, the number of ASMs was reduced in 41% of patients, unchanged in 55% of them and increased in only 4% of them. Successful MRg-LITT for ETLE allows for ASMs reduction in a significant portion of patients and complete ASMs withdrawal in a subset of them. Patients with higher pre-operative seizure frequency or occurrence of acute post operative seizures exhibit higher chances relapse post ASMs reduction.


Repeated exposure to sham testing procedures reduces reflex withdrawal and hot-plate latencies: attenuation of tonic descending inhibition?
Five days' repeated exposure of experimentally naive rats to the experimental environment and to sham nociceptive testing procedures ('habituation') reduced the latency for reflex withdrawal of the hindpaw from hot water (49 degrees C) by 43%, to that of spinalised habituated or novice animals. Hot-plate (50 degrees C) paw lick latencies were reduced equally (40%) by habituation or parachlorophenylalanine, and were increased 32% by D,L-5-hydroxytryptophan. Neither drug affected hot-plate latencies of habituated animals. Naloxone had no effect on flexor withdrawal or hot-plate latencies in either novice or habituated animals. These results suggest that habituation substantially attenuates tonic serotonergic inhibition of spinal nociceptive transmission.


Carbon dots-mediated synthesis of gold nanodendrites with extended absorption into NIR-II window for in vivo photothermal therapy.
Photothermal therapy (PTT) in the second near-infrared (NIR-II) window has attracted extensive attention due to the benefits in high maximum permissible exposure and penetration depth. Current photothermal agents generally show a broadband absorption accompanied by a gradual attenuation of absorption in the NIR-II window, leading to poor effect of PTT. It remains a great challenge to gain photothermal agents with strong and characteristic absorption in NIR-II regions. To overcome this problem, based on carbon dots (CDs)-mediated growth strategy, we proposed a simple and feasible approach to prepare plasmonic gold nanodendrites (AuNDs) with NIR-II absorption to enhance the therapeutic effect of PTT. By rationally regulating the size and branch length of AuNDs, the AuNDs exhibited a broadband absorption from 300 to 1350 nm, with two characteristic absorption peaks located at 1077 and 1265 nm. The AuNDs demonstrated desired optical photothermal conversion efficiency (38.0%), which was further applied in NIR-II photoacoustic imaging (PAI) and PTT in human colon cancer cells (HCT 116)-tumor-bearing mice model. The tumor cells could be effectively eliminated in vivo under 1064 nm laser irradiation by the guidance of PAI. We reported a simple but powerful synthetic method to obtain the unique AuNDs with strong and characteristic absorption peaks in the NIR-II window. This study provides a promising solution to tuning the growth of nanoparticles for bioimaging and phototherapy in the NIR-II window.


In vivo genotoxicity of nitrates and nitrites in germ cells of male mice. I. Evidence for gonadal exposure and lack of heritable effects.
Effects of nitrate (doses of 600 and 1200 mg/kg/day during 14 days) and sodium nitrite (60 and 120 mg/kg/day during 14 days) on germ cells of male mice were investigated. The mode of application was stomach intubation. The germ cell stages analysed were spermatids (for the heritable effects) and differentiating and stem-cell spermatogonia (for direct effects). A lack of heritable translocations, sperm abnormalities, as well as morphological changes, such as changes in eyes, coat colour, testes and body weight, was demonstrated in F1 males originating from treated P males. Significant effects in treated males were found with respect to: (1) sex-chromosomal univalency in the diakinesis-methaphase I stage after the treatment of stem spermatogonia (both doses of sodium nitrate and the higher dose of sodium nitrite), (2) sperm-head abnormalities after treatment of differentiating spermatogonia (the higher dose of sodium nitrate and both doses of sodium nitrite), and (3) fertility after treatment of spermatids (the higher dose of sodium nitrite). Nonmutagenic effects and possible carcinogenic potential of the tested doses are discussed.


Treatment options for transposition of the great arteries with ventricular septal defect complicated by pulmonary vascular obstructive disease.
The arterial switch operation is the procedure of choice for patients with isolated transposition of the great arteries or those with associated atrial and/or ventricular septal defects. After the development of pulmonary arterial hypertension, the surgical options for patients with a late presentation include either retraining the left ventricle by pulmonary artery banding followed by an arterial switch operation or palliative atrial or arterial switch, with or without medical management of pulmonary hypertension. We present a case with D-transposition of the great arteries with ventricular septal defects and irreversible pulmonary arterial hypertension who improved after a palliative atrial switch operation.


Roles of long, non-coding RNA in chromosome-wide transcription regulation: lessons from two dosage compensation systems.
A large part of higher eukaryotic genomes is transcribed into RNAs lacking any significant open reading frame. This "non-coding part" has been shown to actively contribute to regulating gene expression, but the mechanisms are largely unknown. Particularly instructive examples are provided by the dosage compensation systems, which assure that the single X chromosome in male cells and the two X chromosomes in female cells give rise to similar amounts of gene product. Although this is achieved by very different strategies in mammals and fruit flies, long, non-coding RNAs (lncRNAs) are involved in both cases. Here we summarize recent progress towards unraveling the mechanisms, by which the Xist and roX RNAs mediate the selective association of regulators with individual target chromosomes, to initiate dosage compensation in mammals and fruit flies, respectively.


Corrigendum to "Rituximab versus mitoxantrone: comparing effectiveness and safety in advanced relapsing multiple sclerosis".
[This corrects the article DOI: 10.1177/20406223211024366.].


Leveraging cellular mechano-responsiveness for cancer therapy.
Cells sense the biophysical properties of the tumor microenvironment (TME) and adopt these signals in their development, progression, and metastatic dissemination. Recent work highlights the mechano-responsiveness of cells in tumors and the underlying mechanisms. Furthermore, approaches to mechano-modulating diverse types of cell have emerged aiming to inhibit tumor growth and metastasis. These include targeting mechanosensitive machineries in cancer cells to induce apoptosis, intervening matrix stiffening incurred by cancer-associated fibroblasts (CAFs) in both primary and metastatic tumor sites, and modulating matrix mechanics to improve immune cell therapeutic efficacy. This review is envisaged to help scientists and clinicians in cancer research to advance understanding of the cellular mechano-responsiveness in TME, and to harness these concepts for cancer mechanotherapies.


Current practices in generation of small molecule new leads.
The current drug discovery processes in many pharmaceutical companies require large and growing collections of high quality lead structures for use in high throughput screening assays. Collections of small molecules with diverse structures and "drug-like" properties have, in the past, been acquired by several means: by archive of previous internal lead optimization efforts, by purchase from compound vendors, and by union of separate collections following company mergers. More recently, many drug discovery companies have established dedicated efforts to effect synthesis by internal and/or outsourcing efforts of targeted compound libraries for new lead generation. Although high throughput/combinatorial chemistry is an important component in the process of new lead generation, the selection of library designs for synthesis and the subsequent design of library members has evolved to a new level of challenge and importance. The potential benefits of screening multiple small molecule compound library designs against multiple biological targets offers substantial opportunity to discover new lead structures. Subsequent optimization of such compounds is often accelerated because of the structure-activity relationship (SAR) information encoded in these lead generation libraries. Lead optimization is often facilitated due to the ready applicability of high-throughput chemistry (HTC) methods for follow-up synthesis. Some of the strategies, trends, and critical issues central to the success of lead generation processes are discussed below.


Suprasellar paraganglioma: a case report and review of the literature.
Paragangliomas arising in the suprasellar region are extremely rare. We report a case of suprasellar paraganglioma in a 47-year-old man who presented with amnesia and impaired visual acuity without any endocrine dysfunction. Magnetic resonance imaging (MRI) showed a large enhancing tumour in the suprasellar area. Following subtotal surgical excision, the diagnosis of paraganglioma was confirmed by pathology. In this case report we describe the MRI pattern of suprasellar paraganglioma and review the literature of this uncommon lesion.


The Role of Minimally Invasive Percutaneous Pedicle Screw Fixation for the Management of Spinal Metastatic Disease.
Optimal surgical management of spinal metastatic disease remains controversial. Skip and diffuse spinal lesions, patient frailty, and the need for timely adjuvant chemoradiation complicate surgical decision-making. Minimally invasive percutaneous pedicle screw fixation (MIPSF) is an attractive concept that can confer stability and allow early postoperative mobilization. To date, outcomes of the MIPSF technique remain under-investigated. A single-center retrospective review of patients undergoing percutaneous instrumentation for multilevel spinal metastatic disease between January 2012 and October 2020 was performed. Twenty-four patients were identified, and their primary tumor diagnoses, modified Tokuhashi scores, Spine Instability Neoplastic Scores, neurologic functions, pain scores, and procedure types were noted. Of these patients, 17 underwent fixation of 6 or more levels (L-MIPSF), whereas 7 underwent fixation of <6 levels (S-MIPSF). All patients had screw-and-rod constructs placed percutaneously using bi-planar fluoroscopy guidance. Patients undergoing corpectomy, multilevel laminectomies, or open posterior instrumentation were excluded. Improvement in pain and neurological function was noted in nearly all patients who underwent MIPSF. Average skin incision-to-closing time was 130 minutes, and standard deviation of 55 minutes. Likewise, the average estimated operative blood loss was 402 mL, and standard deviation of 388 mL. Only one patient required hardware revision due to proximal loss of fixation. Two patients required mini-open decompression procedures due to tumor recurrence at different levels than the index pathology. Multilevel minimally invasive spinal fixation is feasible in patients with diffuse spinal metastasis. The percutaneous nature of the technique minimizes dissection, blood loss, and operative times. Early outcomes of MIPSF are promising and demonstrate utility in avoiding multiple subsequent procedures in a cohort of deconditioned patients.


Percutaneous nephrolithotomy for renal stones following failed extracorporeal shockwave lithotripsy: different performances and morbidities.
The purpose of this study is to summarize the results of percutaneous nephrolithotomy (PCNL) for renal stones following failed extracorporeal shockwave lithotripsy (SWL), and to investigate the effect of previous SWL on the performances and morbidities of subsequent PCNL. Sixty-two patients with a history of failed SWL who underwent PCNL on the same kidney (group 1) were compared to 273 patients who had received PCNL as first treatment choice (group 2). Patient demographics, stone characteristics, operative findings, and complications were documented and compared. Groups 1 and 2 had similar patient demographics and stone characteristics. Mean time to establish access was comparable in both groups (10.5 ± 4.2 vs. 9.6 ± 4.5 min, p = 0.894). Time required to remove stones and total operative time were longer in group 1 (71.5 ± 10.3 vs. 62.3 ± 8.6 min, p = 0.011 and 95.8 ± 12.0 vs. 80.6 ± 13.2 min., p = 0.018, respectively). Group 1 had lower clearance rate compared to group 2 (83.9 vs. 93.4 %, p = 0.021), while postoperative complications were similar in both groups. Scattered stone fragments buried within the tissues made the procedure more difficult for stone fragmenting and extracting, which lead to longer operative time and inferior stone free rate. However, the PCNL procedure was safe and effective in patients with failed SWL. The risk of complications was similar and clearance rate was encouraging.


Sex-specific environmental influences affecting MS development.
Vitamin D status, smoking, and Epstein-Barr virus infection (EBV) may all contribute to explain differences in disease prevalence and incidence of Multiple Sclerosis (MS). MS affects women more often than men, and recent cross-sectional study assessments provide evidence of increased female to male prevalence in relapsing remitting MS patients, suggesting that sex hormones may exert an active role in disease pathogenesis. Studies in both humans and animal disease models demonstrate a functional synergy for the immunomodulatory effects of Vitamin D3 and 17-β estradiol. Both smoking and EBV infection clearly increase MS risk, and smoking history has also been associated with poorer disease prognosis. However, neither factor can explain the recent trend indicating greater female prevalence. Therefore, large population-based case-control studies from well defined geographic areas with homogeneous populations should be performed, in order to define environmental factor effects, and sex hormone influences, to better understand prevalence and incidence gender differences observed.