An integrated single-cell reference atlas of the human endometrium.

The complex and dynamic cellular composition of the human endometrium remains poorly understood. Previous endometrial single-cell atlases profiled few donors and lacked consensus in defining cell types. We introduce the Human Endometrial Cell Atlas (HECA), a high-resolution single-cell reference atlas (313,527 cells) combining published and new endometrial single-cell transcriptomics datasets of 63 women with and without endometriosis. HECA assigns consensus and identifies previously unreported cell types, mapped in situ using spatial transcriptomics and validated using a new independent single-nuclei dataset (312,246 nuclei, 63 donors). In the functionalis, we identify intricate stromal-epithelial cell coordination via transforming growth factor beta (TGFß) signaling. In the basalis, we define signaling between fibroblasts and an epithelial population expressing progenitor markers. Integration of HECA with large-scale endometriosis genome-wide association study data pinpoints decidualized stromal cells and macrophages as most likely dysregulated in endometriosis. The HECA is a valuable resource for studying endometrial physiology and disorders, and for guiding microphysiological in vitro systems development.

Correlation between neural response telemetry measurements and fitting levels.

INTRODUCTION: The neural response telemetry (NRT) is a standard procedure in cochlear implantation mostly used to determine the functionality of implanted device and to check auditory nerve responds to the stimulus. Correlation between NRT measurements and subjective threshold (T) and maximum comfort (C) levels has been reported but results are inconsistent, and it is still not clear which of the NRT measurements could be the most useful in predicting fitting levels. PURPOSE: In our study we aimed to investigate which NRT measurement corresponds better to fitting levels. Impedance (IMP), Evoked Action Potential (ECAP) threshold and amplitude growth function (AGF) slope values were included in the study. Also, we tried to identify cochlear area at which the connection between NRT measurements and fitting levels would be the most pronounced. MATERIALS AND METHODS: Thirty-one children implanted with Cochlear device were included in this retrospective study. IMP, ECAP thresholds and AGF were obtained intra-operatively and 12 months after surgery at electrodes 5, 11 and 19 as representative for each part of cochlea. Subjective T and C levels were obtained 12 months after the surgery during cochlear fitting. RESULTS: ECAP thresholds obtained 12 months after surgery showed statistically significant correlation to both T and C levels at all 3 selected electrodes. IMP correlated with C levels while AGF showed tendency to correlate with T levels. However, these correlations were not statistically significant for all electrodes. CONCLUSION: ECAP threshold measurements correlated to T and C values better than AGF slope and IMP. Measurements obtained twelve months after surgery seems to be more predictive of T and C values compared to intra-operative measurements. The best correlation between ECAP threshold and T and C values was found at electrode 11 suggesting NRT measurements at mid-portion cochlear region to be the most useful in predicting fitting levels.

Acute response to pathogens in the early human placenta at single-cell resolution.

The placenta is a selective maternal-fetal barrier that provides nourishment and protection from infections. However, certain pathogens can attach to and even cross the placenta, causing pregnancy complications with potential lifelong impacts on the child's health. Here, we profiled at the single-cell level the placental responses to three pathogens associated with intrauterine complications-Plasmodium falciparum, Listeria monocytogenes, and Toxoplasma gondii. We found that upon exposure to the pathogens, all placental lineages trigger inflammatory responses that may compromise placental function. Additionally, we characterized the responses of fetal macrophages known as Hofbauer cells (HBCs) to each pathogen and propose that they are the probable niche for T. gondii. Finally, we revealed how P. falciparum adapts to the placental microenvironment by modulating protein export into the host erythrocyte and nutrient uptake pathways. Altogether, we have defined the cellular networks and signaling pathways mediating acute placental inflammatory responses that could contribute to pregnancy complications.

Robust temporal map of human in vitro myelopoiesis using single-cell genomics.

Myeloid cells are central to homeostasis and immunity. Characterising in vitro myelopoiesis protocols is imperative for their use in research, immunotherapies, and understanding human myelopoiesis. Here, we generate a >470K cells molecular map of human induced pluripotent stem cells (iPSC) differentiation into macrophages. Integration with in vivo single-cell atlases shows in vitro differentiation recapitulates features of yolk sac hematopoiesis, before definitive hematopoietic stem cells (HSC) emerge. The diversity of myeloid cells generated, including mast cells and monocytes, suggests that HSC-independent hematopoiesis can produce multiple myeloid lineages. We uncover poorly described myeloid progenitors and conservation between in vivo and in vitro regulatory programs. Additionally, we develop a protocol to produce iPSC-derived dendritic cells (DC) resembling cDC2. Using CRISPR/Cas9 knock-outs, we validate the effects of key transcription factors in macrophage and DC ontogeny. This roadmap of myeloid differentiation is an important resource for investigating human fetal hematopoiesis and new therapeutic opportunities.

COMPARISON OF HEARING OUTCOMES AFTER STAPES SURGERY DEPENDING ON PROSTHESIS TYPE: A RETROSPECTIVE ANALYSIS.

Stapes surgery is generally performed to treat otosclerosis, and there are numerous surgical techniques and prosthesis materials available. Critical evaluation of postoperative hearing outcomes is crucial for identification and further improvement of treatment options. This study is a non-randomized retrospective analysis of hearing threshold levels before and after stapedectomy or stapedotomy in 365 patients during a twenty-year period. The patients were classified into three groups depending on the prosthesis and surgery type: stapedectomy with Schuknecht prosthesis placement and stapedotomy with either Causse or Richard prosthesis. The postoperative air-bone gap (ABG) was calculated by subtracting the bone conduction pure tone-audiogram (PTA) from the air conduction PTA. Hearing threshold levels were evaluated preoperatively and postoperatively from 250 Hz to 12 kHz. The results showed air-bone gap reduction <10 dB in 72% patients, 70% of patients, and 76% of patients using Schucknecht's prosthesis, Richard prosthesis, and Causse prosthesis, respectively. The results did not differ significantly between three prothesis types. Choice of prosthesis should be made individually for each patient, but surgeon competency is still the most important outcome variable, regardless of prosthesis type.

Salivary cortisone as potential predictor of occupational exposure to noise and related stress.

Salivary cortisone strongly correlates with serum cortisol, and since it is less invasive to measure salivary cortisone than serum cortisol and easier than to measure cortisol in saliva, as its concentrations are much lower, we wanted to compare salivary cortisone and cortisol levels as markers of noise-induced stress reaction. The study included 104 participants aged 19-30 years, 50 of whom were exposed to occupational noise ≥85 dB(A) and 54 non-exposed, control students. All participants took samples of their saliva with Salivette® Cortisol synthetic swabs on three consecutive working days first thing in the morning. Salivary cortisone and cortisol levels were determined with high-performance liquid chromatography. In addition, they completed a 10-item Perceived Stress Scale (PSS-10) questionnaire, and occupationally noise-exposed participants also completed the Health and Safety Executive (HSE) questionnaire on occupational psychosocial risks. The exposed participants had significantly higher cortisone (P<0.001) and cortisol (P<0.001) levels than controls, and the correlation between cortisone and cortisol levels in the exposed participants was strong (ϱ =0.692, P<0.001), which suggests that salivary cortisone can replace cortisol measurements in saliva as a more reliable method than salivary cortisol and less invasive than serum cortisol. However, the level of perceived stress scored on PSS-10 in the exposed participants did not differ significantly from stress reported by controls, but correlated negatively with cortisone levels, which is contrary to our expectations and raises questions as to why.

Significance of intraoperative findings in revision tympanomastoidectomy.

PURPOSE: The study was designed to assess correlations between intraoperative findings in revision tympanomastoidectomy as predictors of cholesteatoma recurrence. MATERIALS AND METHODS: A retrospective single-institution cohort of 101 patients who underwent surgical treatment for recurrent chronic otitis media in a tertiary referral otology centre. RESULTS: Out of 101 patients, 65 had canal wall up and 36 canal wall down revision surgery. There were 35 cholesteatoma recurrences. Sites most commonly associated with recurrent disease were residual facial ridge cells in 46 (45.5%), ossicular chain sites in 46 (45.5%) patients, posterior external auditory canal wall erosions in 38 (37.6%) patients and mastoid apex recurrence in 35 (34.7%) patients. Ossicular and posterior external auditory canal wall erosion and incomplete removal of mastoid apex cells correlate well with cholesteatoma recurrence accompanied by canal wall up surgery (p=0.009). Residual mastoid apex cells, posterior external auditory canal wall erosion and presence of residual facial ridge cells were identified as the strongest positive predictors of cholesteatoma recurrence, identifying high risk patients associated with canal wall down procedures (p=0.0036). CONCLUSIONS: Correlations between intraoperative findings and cholesteatoma recurrence could improve preoperative and intraoperative planning and reduce the rates of postoperative failures1 due to mismanagement of high risk areas.

Breast and gynecological cancers in Croatia, 1988-2008.

AIM: To analyze and interpret incidence and mortality trends of breast and ovarian cancers and incidence trends of cervical and endometrial cancers in Croatia for the period 1988-2008. METHODS: Incidence data were obtained from the Croatian National Cancer Registry. Themortality data were obtained from the World Health Organization (WHO) mortality database. Trends of incidence and mortality were analysed by joinpoint regression analysis. RESULTS: Joinpoint analysis showed an increase in the incidence of breast cancer with estimated annual percent of change (EAPC) of 2.6% (95% confidence interval [CI], 1.9 to 3.4). The mortality rate was stable, with the EAPC of 0.3%. Endometrial cancer showed an increasing incidence trend, with EAPC of 0.8% (95% CI, 0.2 to 1.4), while cervical cancer showed a decreasing incidence trend, with EAPC of -1.0 (95% CI, -1.6 to -0.4). Ovarian cancer incidence showed three trends, but the average annual percent change (AAPC) for the overall period was not significant, with a stable trend of 0.1%. Ovarian cancer mortality was increasing since 1992, with EAPC of 1.2% (95% CI, 0.4 to 1.9), while the trend for overall period was stable with AAPC 0.1%. CONCLUSION: Incidence trends of breast, endometrial, and ovarian cancers in Croatia 1988-2008 are similar to the trends observed in most of the European countries, while the modest decline in cervical cancer incidence and lack of decline in breast cancer mortality suggest suboptimal cancer prevention and control.

OSVZ progenitors of human and ferret neocortex are epithelial-like and expand by integrin signaling.

A major cause of the cerebral cortex expansion that occurred during evolution is the increase in subventricular zone (SVZ) progenitors. We found that progenitors in the outer SVZ (OSVZ) of developing human neocortex retain features of radial glia, in contrast to rodent SVZ progenitors, which have limited proliferation potential. Although delaminating from apical adherens junctions, OSVZ progenitors maintained a basal process contacting the basal lamina, a canonical epithelial property. OSVZ progenitor divisions resulted in asymmetric inheritance of their basal process. Notably, OSVZ progenitors are also found in the ferret, a gyrencephalic nonprimate. Functional disruption of integrins, expressed on the basal process of ferret OSVZ progenitors, markedly decreased the OSVZ progenitor population size, but not that of other, process-lacking SVZ progenitors, in slice cultures of ferret neocortex. Our findings suggest that maintenance of this epithelial property allows integrin-mediated, repeated asymmetric divisions of OSVZ progenitors, providing a basis for neocortical expansion.