Education Team Time Out in Oncologic Visceral Surgery Optimizes Surgical Resident Training and Team Communication-Results of a Prospective Trial.

BACKGROUND: Surgical education is highly dependent on intraoperative communication. Trainers must know the trainee's training level to ensure high-quality surgical training. A systematic preoperative dialogue (Educational Team Time Out, ETO) was established to discuss the steps of each surgical procedure. METHODS: Over 6 months, ETO was performed within a time limit of 3 minutes. Digital surveys on the utility of ETO and its impact on performance were conducted immediately after surgery and at the end of the study period among the staff of the participating disciplines (trainer, trainee, surgical nursing staff, anaesthesiologists, and medical students). The number of surgical substeps performed was recorded and compared with the equivalent period one year earlier. RESULTS: ETO was performed in 64 of the 103 eligible operations (62%). Liver resection (n = 37) was the most frequent procedure, followed by left-sided colorectal surgery (n = 12), partial pancreaticoduodenectomy (n = 6), right-sided hemicolectomies (n = 5), and thyroidectomies (n = 4). Anaesthesiologists most frequently reported that ETO had a direct impact on their work during surgery (90.9%). The influence scores were 46.8% for trainees, 8.8% for trainers, 53.3% for surgical nursing staff and 66.6% for medical students. During the implementation of ETO, a trend towards more assisted substeps in oncologic visceral surgery was seen compared to the corresponding period one year earlier (51% vs.40%; p = 0.11). CONCLUSION: ETO leads to improved intraoperative communication and more performed substeps during complex procedures, which increases motivation and practical training. This concept can easily be implemented in all surgical specialties to improve surgical education.

General, spinal or regional anaesthesia does not affect strength performance 6 months after ACL reconstruction.

PURPOSE: The recovery of strength is a key element in successfully returning to sports after ACL reconstruction. The type of anaesthesia has been suspected an influential factor in the post-operative recovery of muscle function. METHODS: In this retrospective analysis, n = 442 consecutive patients undergoing primary isolated ACL reconstruction using a hamstring autograft were analysed by pre- and post-operative isokinetic tests in a single orthopaedic centre. These were subdivided into four cohorts: (1) general anaesthesia (n = 47), (2) general anaesthesia with prolonged (48 h) on-demand femoral nerve block (n = 37), (3) spinal anaesthesia (n = 169) and (4) spinal anaesthesia with prolonged (48 h) on-demand femoral nerve block (n = 185). Primary outcome was the change from pre- to post-operative isokinetic strength during knee extension and flexion. RESULTS: Using one-way ANOVA, there was no significant influence of the type of anaesthesia. The main effect of anaesthesia on change in extension forces was not significant, and effect sizes were very small (n.s.). Similarly, the main effect of anaesthesia on change in flexion forces was statistically not significant (n.s.). CONCLUSIONS: The findings of this study support the interpretation that the type of anaesthesia has no significant effect on the ability to recover thigh muscle strength 6 months after isolated hamstring ACL reconstruction. With regard to the recovery of athletic performance and return-to-sports testing criteria, there is no reason to avoid regional anaesthesia. LEVEL OF EVIDENCE: III.

Perspectives in linear accelerator for FLASH VHEE: Study of a compact C-band system.

PURPOSE: In order to translate the FLASH effect in clinical use and to treat deep tumors, Very High Electron Energy irradiations could represent a valid technique. Here, we address the main issues in the design of a VHEE FLASH machine. We present preliminary results for a compact C-band system aiming to reach a high accelerating gradient and high current necessary to deliver a Ultra High Dose Rate with a beam pulse duration of 3µs. METHODS: The proposed system is composed by low energy high current injector linac followed by a high acceleration gradient structure able to reach 60-160 MeV energy range. To obtain the maximum energy, an energy pulse compressor options is considered. CST code was used to define the specifications RF parameters of the linac. To optimize the accelerated current and therefore the delivered dose, beam dynamics simulations was performed using TSTEP and ASTRA codes. RESULTS: The VHEE parameters Linac suitable to satisfy FLASH criteria were simulated. Preliminary results allow to obtain a maximum energy of 160 MeV, with a peak current of 200 mA, which corresponds to a charge of 600 nC. CONCLUSIONS: A promising preliminary design of VHEE linac for FLASH RT has been performed. Supplementary studies are on going to complete the characterization of the machine and to manufacture and test the RF prototypes.

Validation of DREADD agonists and administration route in a murine model of sleep enhancement.

BACKGROUND: Chemogenetics is a powerful tool to study the role of specific neuronal populations in physiology and diseases. Of particular interest, in mice, acute and specific activation of parafacial zone (PZ) GABAergic neurons expressing the Designer Receptors Activated by Designer Drugs (DREADD) hM3Dq (PZGABA-hM3Dq) enhances slow-wave-sleep (SWS), and this effect lasts for up to 6 h, allowing prolonged and detailed study of SWS. However, the most widely used DREADDs ligand, clozapine N-oxide (CNO), is metabolized into clozapine which has the potential of inducing non-specific effects. In addition, CNO is usually injected intraperitoneally (IP) in mice, limiting the number and frequency of repeated administration. NEW METHODS: The present study is designed to validate the use of alternative DREADDs ligands-deschloroclozapine (DCZ) and compound 21 (C21)-and a new administration route, the voluntary oral administration. RESULTS: We show that IP injections of DCZ and C21 dose-dependently enhance SWS in PZGABA-hM3Dq mice, similar to CNO. We also show that oral administration of CNO, DCZ and C21 induces the same sleep phenotype as compared with IP injection. COMPARISON WITH EXISTING METHODS AND CONCLUSION: Therefore, DCZ and C21 are powerful alternatives to the use of CNO. Moreover, the voluntary oral administration is suitable for repeated dosing of DREADDs ligands.

Two novel mouse models of slow-wave-sleep enhancement in aging and Alzheimer's disease.

Aging and Alzheimer's disease (AD) are both associated with reduced quantity and quality of the deepest stage of sleep, called slow-wave-sleep (SWS). Slow-wave-sleep deficits have been shown to worsen AD symptoms and prevent healthy aging. However, the mechanism remains poorly understood due to the lack of animal models in which SWS can be specifically manipulated. Notably, a mouse model of SWS enhancement has been recently developed in adult mice. As a prelude to studies assessing the impact of SWS enhancement on aging and neurodegeneration, we first asked whether SWS can be enhanced in animal models of aging and AD. The chemogenetic receptor hM3Dq was conditionally expressed in GABAergic neurons of the parafacial zone of aged mice and AD (APP/PS1) mouse model. Sleep-wake phenotypes were analyzed in baseline condition and following clozapine-N-oxide (CNO) and vehicle injections. Both aged and AD mice display deficits in sleep quality, characterized by decreased slow wave activity. Both aged and AD mice show SWS enhancement following CNO injection, characterized by a shorter SWS latency, increased SWS amount and consolidation, and enhanced slow wave activity, compared with vehicle injection. Importantly, the SWS enhancement phenotypes in aged and APP/PS1 model mice are comparable to those seen in adult and littermate wild-type mice, respectively. These mouse models will allow investigation of the role of SWS in aging and AD, using, for the first time, gain-of SWS experiments.

Attosecond intra-valence band dynamics and resonant-photoemission delays in W(110).

Time-resolved photoelectron spectroscopy with attosecond precision provides new insights into the photoelectric effect and gives information about the timing of photoemission from different electronic states within the electronic band structure of solids. Electron transport, scattering phenomena and electron-electron correlation effects can be observed on attosecond time scales by timing photoemission from valence band states against that from core states. However, accessing intraband effects was so far particularly challenging due to the simultaneous requirements on energy, momentum and time resolution. Here we report on an experiment utilizing intracavity generated attosecond pulse trains to meet these demands at high flux and high photon energies to measure intraband delays between sp- and d-band states in the valence band photoemission from tungsten and investigate final-state effects in resonant photoemission.

Infection rate and complications after 621 transperineal MRI-TRUS fusion biopsies in local anesthesia without standard antibiotic prophylaxis.

PURPOSE: The aim of this study was to assess the post biopsy infection rate, feasibility and prostate cancer (PCa) detection rate (CDR) by performing transperineal MRI-TRUS fusion biopsy of the prostate (TPBx) under local anesthesia (LA) without antibiotic prophylaxis (AP). METHODS: We prospectively screened 766 men with suspicious lesions on mpMRI, an elevated PSA level or a suspect digital examination undergoing MRI-TRUS-TPBx in LA, from May 2019 to July 2020. Patients with the need for antibiotic prophylaxis or without a PI-RADS target lesion were excluded from final analyses. We reported CDR, perioperative pain (0-10) and postoperative complications. PCa with an ISUP grade ≥ 2 was classified as clinically significant PCa (csPCa). RESULTS: We included 621 patients with a median age of 68 years (IQR 62-74), a PSA of 6.43 ng/mL (IQR 4.72-9.91) and a prostate volume of 45 cc (IQR 32-64). In median, 4 targeted (TB) (IQR 3-4) and 6 (IQR 5-7) systematic biopsies (SB) detected in combination overall 416 (67%) PCa and 324 (52%) csPCa. Overall CDR of TB for PI-RADS 3, 4 and 5 was 26%, 65% and 84%, respectively. Patients reported a median perioperative pain level of 2 (IQR 1-3). Four patients (0.6%) developed a post biopsy infection, one experienced urosepsis. CONCLUSION: Our results demonstrate that transperineal MRI-TRUS fusion-guided prostate biopsy under LA without AP is feasible, safe and well tolerated.

Paternal exposure to morphine during adolescence potentiates morphine withdrawal in male offspring: Involvement of the lateral paragigantocellularis nucleus.

BACKGROUND: Opiate exposure during adolescence perturbs the brain's maturation process and potentially confers long-term adverse consequences, not only in exposed individuals but also in their posterity. Here, we investigate the outcomes of adolescent paternal morphine exposure on morphine withdrawal profile in male offspring. METHODS: Male Wistar rats were chronically subjected to 10 days of an escalating regimen of morphine during adolescence. After a 20-day washout period, adult males were allowed to copulate with naïve females. The adult male offspring were tested for somatic and affective components of naloxone-precipitated morphine withdrawal using conditioned place aversion. Moreover, electrical activity of the lateral paragigantocellularis (LPGi) nucleus, which is involved in development of opiate dependence, was recorded in response to a challenge dose of morphine via extracellular single-unit recordings. RESULTS: Morphine-sired offspring exhibited augmented expression of naloxone-induced somatic and affective signs of opiate withdrawal compared to the control saline-sired counterparts. In vivo recording revealed that LPGi neurons displayed heterogeneous responses (inhibitory, excitatory, and no change) to acute morphine administration in both morphine- and saline-sired animals. The morphine-induced discharge inhibition was potentiated in morphine-sired offspring. However, the extent of discharge excitation in response to morphine did not reach significance in these subjects. Moreover, the lack of alteration in maternal behavior toward morphine-sired offspring indicates that this is due to germline-dependent transmission of epigenetic traits across generations. CONCLUSIONS: Preconception paternal exposure to morphine during adolescence potentiates opiate withdrawal signs in male offspring which is mediated, at least in part, by epigenetic alteration of LPGi-related brain circuitry.

The neuroanatomy and neurochemistry of sleep-wake control.

Sleep-wake control is dependent upon multiple brain areas widely distributed throughout the neural axis. Historically, the monoaminergic and cholinergic neurons of the ascending arousal system were the first to be discovered, and it was only relatively recently that GABAergic and glutamatergic wake- and sleep-promoting populations have been identified. Contemporary advances in molecular-genetic tools have revealed both the complexity and heterogeneity of GABAergic NREM sleep-promoting neurons as well as REM sleep-regulating populations in the brainstem such as glutamatergic neurons in the sublaterodorsal nucleus. The sleep-wake cycle progresses from periods of wakefulness to non-rapid eye movement (NREM) sleep and subsequently rapid eye movement (REM) sleep. Each vigilance stage is controlled by multiple neuronal populations, via a complex regulation that is still incompletely understood. In recent years the field has seen a proliferation in the identification and characterization of new neuronal populations involved in sleep-wake control thanks to newer, more powerful molecular genetic tools that are able to reveal neurophysiological functions via selective activation, inhibition and lesion of neuroanatomically defined sub-types of neurons that are widespread in the brain, such as GABAergic and glutamatergic neurons.1,2.

[Initial results of perineal MRI/ultrasound fusion biopsies under local anesthesia without standard perioperative antibiotic prophylaxis]. / Etablierung der perinealen MRT­/Ultraschallfusionsbiopsien in Lokalanästhesie ohne standardmäßige, perioperative Antibiotikaprophylaxe.

The perineal approach for prostate biopsy (PB) is a sterile alternative to conventional transrectal PB. Targeted local anesthesia allows perineal prostate biopsy (pPB) to be performed without general anesthesia. This paper presents the first results after establishing perineal MRI/ultrasound fusion biopsy (pFB) under local anesthesia without standard perioperative antibiotic prophylaxis. For this purpose, 144 patients were included in the study after pFB at the Vivantes Klinikum am Urban. No peri-interventional antibiotic prophylaxis was applied. Peri- and postoperatively, the pain sensation, measured using an analogue pain scale from 0-10, and complications were recorded. The median patient age was 68 and the median prostate-specific antigen (PSA) value 7.07 ng/ml. In all, 49% of the patients received primary PB. The overall detection rate for prostate cancer (PCa) was 71% and for PI-RADS 3, 4 and 5 was 44, 71 and 92%, respectively. The median pain sensation during biopsy was 2. Furthermore, 63% of patients with a transrectal prebiopsy considered this to be more painful and another 20% expressed similar pain levels. Only 1 patient developed a febrile urinary tract infection. The pFB of the prostate under local anesthesia without antibiotic, perioperative prophylaxis is a suitable alternative to the transrectal PB with regard to the detection rate of PCa, the side effect profile and the subjective pain perception of the patients during the intervention.

[Surgical treatment of hepatic tumors-liver resection and transplantation]. / Chirurgische Therapie bei Lebertumoren ­ Leberresektion und -transplantation.

The most frequent primary hepatic malignancies are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (intrahepatic cholangiocellular adenocarcinoma [iCCA]). For HCC in cirrhosis, liver transplantation offers the advantage of a complete hepatectomy radically removing all tumorous tissue along with the surrounding cirrhotic parenchyma, which is otherwise associated with a very high risk of recurrence. For HCC in non-cirrhotic livers and iCCA, liver resection is the treatment of choice. Nowadays, even extended resections can be performed with low mortality in experienced centers. Surgical therapy is more and more embedded into multimodal treatment concepts and decision making should be interdisciplinary as for other gastrointestinal tumors.

[New DIN and ISO norms for determination of visual acuity]. / Neue DIN- und ISO-Normen zur Sehschärfebestimmung.

Recently, three international norms (ISO) for visual acuity assessment were revised. The DIN EN ISO 8596:2018 stipulates the Landolt C eye chart as the standard optotype and specifies display characteristics. An informative annex lists clinical optotypes for the first time. These include the ETDRS chart, Snellen chart and pediatric optotypes; however, these clinical optotypes do not have the same status as the Landolt C chart, since even with identical font size and stroke width they may differ in recognizability. The technical report ISO/TR 19498:2015 complements DIN EN ISO 8596. A scientifically appropriate procedure is described, which enables a quantitative correlation of clinical optotypes with the Landolt C chart. The DIN EN ISO 10938:2016 describes the required optical quality of optotypes. For the first time, electronic devices are explicitly approved for standardized visual acuity tests. Consequently, according to this amendment electronic devices may be used for acuity assessment for ophthalmological expert opinions according to DIN 58220, part 3.

Differential Role of Pontomedullary Glutamatergic Neuronal Populations in Sleep-Wake Control.

Parafacial zone (PZ) GABAergic neurons play a major role in slow-wave-sleep (SWS), also called non-rapid eye movement (NREM) sleep. The PZ also contains glutamatergic neurons expressing the vesicular transporter for glutamate, isoform 2 (Vglut2). We hypothesized that PZ Vglut2-expressing (PZVglut2) neurons are also involved in sleep control, playing a synergistic role with PZ GABAergic neurons. To test this hypothesis, we specifically activated PZVglut2 neurons using the excitatory chemogenetic receptor hM3Dq. Anatomical inspection of the injection sites revealed hM3Dq transfection in PZ, parabrachial nucleus (PB), sublaterodorsal nucleus (SLD) or various combinations of these three brain areas. Consistent with the known wake- and REM sleep-promoting role of PB and SLD, respectively, chemogenetic activation of PBVglut2 or SLDVglut2 resulted in wake or REM sleep enhancement. Chemogenetic activation of PZVglut2 neurons did not affect sleep-wake phenotype during the mouse active period but increased wakefulness and REM sleep, similar to PBVglut2 and SLDVglut2 activation, during the rest period. To definitively confirm the role of PZVglut2 neurons, we used a specific marker for PZVglut2 neurons, Phox2B. Chemogenetic activation of PZPhox2B neurons did not affect sleep-wake phenotype, indicating that PZ glutamatergic neurons are not sufficient to affect sleep-wake cycle. These results indicate that PZ glutamatergic neurons are not involved in sleep-wake control.

[Lymphadenectomy in oncological visceral surgery-Part 1 : Hepatobiliary tumors and pancreatic cancer]. / Lymphadenektomie in der onkologischen Viszeralchirurgie ­ Teil 1 : Hepatobiliäre Tumoren und Pankreaskarzinom.

Lymphadenectomy is an integral component of the oncological surgery of cancer of the gastrointestinal tract and the hepato-pancreato-biliary system. The lymph node dissection is mainly prognostic but may also offer therapeutic advantages in the treatment of most cancers. Moreover, lymphadenectomy enables an accurate TNM staging, which is essential for a further stratification of the individual treatment as well as the inclusion in clinical trials on adjuvant therapy. This article gives an overview of the anatomy of the lymphatic drainage system of visceral organs and summarizes the current role of a systematic lymphadenectomy in oncological surgery (Part 1: hepatobiliary tumors and pancreatic cancer).

High-flux ultrafast extreme-ultraviolet photoemission spectroscopy at 18.4 MHz pulse repetition rate.

Laser-dressed photoelectron spectroscopy, employing extreme-ultraviolet attosecond pulses obtained by femtosecond-laser-driven high-order harmonic generation, grants access to atomic-scale electron dynamics. Limited by space charge effects determining the admissible number of photoelectrons ejected during each laser pulse, multidimensional (i.e. spatially or angle-resolved) attosecond photoelectron spectroscopy of solids and nanostructures requires high-photon-energy, broadband high harmonic sources operating at high repetition rates. Here, we present a high-conversion-efficiency, 18.4-MHz-repetition-rate cavity-enhanced high harmonic source emitting 5 × 105 photons per pulse in the 25-to-60-eV range, releasing 1 × 1010 photoelectrons per second from a 10-µm-diameter spot on tungsten, at space charge distortions of only a few tens of meV. Broadband, time-of-flight photoelectron detection with nearly 100% temporal duty cycle evidences a count rate improvement between two and three orders of magnitude over state-of-the-art attosecond photoelectron spectroscopy experiments under identical space charge conditions. The measurement time reduction and the photon energy scalability render this technology viable for next-generation, high-repetition-rate, multidimensional attosecond metrology.

Preoperative endoscopic pyloric balloon dilatation decreases the rate of delayed gastric emptying after Ivor-Lewis esophagectomy.

Delayed gastric emptying (DGE) after Ivor-Lewis esophagectomy occurs postoperatively in up to 50% of the patients. This pyloric dysfunction can lead to severe secondary complications postoperatively such as early aspiration, pneumonia or may even have an impact on anastomotic healing and therefore leakage. Early detection of DGE is essential to prevent further complications. The common treatment postoperatively is endoscopic pyloric balloon dilatation (EPBD) after symptoms already occurred. In our work, we analyzed patients who received a preoperative EPBD during the routine restaging endoscopy and compared those patients to a control group to analyze if preoperative EPBD may prevent postoperative DGE and secondary additional complications. We performed a single-center retrospective analysis of 115 patients who received an Ivor-Lewis esophagectomy by the same surgeon between June 2015 and October 2017. Out of these 115 patients, 91 (79.1%) patients received EPBD preoperatively during the staging/restaging endoscopy (PDG, pyloric dilatation group). In 24 (20.9%) patients, preoperative EPBD was not performed due to stenotic esophageal tumors or logistic reasons (NDG, non-pyloric dilatation group). Data of the PDG and NDG group were compared regarding the rate of postoperative DGE as well as DGE and EPBD related complications. In total, 21 (18.3%) patients developed pyloric dysfunction requiring a total of 27 EPBD during follow-up. There were 12 (13.2%) patients in the PDG and 9 (37.5%) patients in the NDG (p = 0.014), respectively. DGE-related complications such as anastomotic leaks (p = 0.466), pulmonary complications (p = 0.466) and longer median hospital stay (p = 0.685) were more frequent in the NDG group; however this difference did not reach statistical significance. The success rate for postoperative EPBD with 20-mm balloons was lower (58.5%) compared to the usage of 30-mm balloons (93.3%). All pre- and postoperative EPBD were performed without any complications. Preoperative EPBD is feasible, safe and can be combined with restating endoscopy. It seems that preoperative EPBD reduces the incidence of DGE and can prevent the need for early postoperative endoscopic interventions. Our recommendation is therefore to perform an EPBD preoperatively when possible to reduce postoperative complications to a minimum. For postoperative EPBD, we recommend the use of the 30-mm balloon due to lower redilatation rates.

[Indications for transplantation and bridging procedures for primary hepatobiliary malignancies]. / Transplantationsindikation und Bridging-Verfahren bei primären hepatobiliären Malignomen.

Primary hepatobiliary malignancies are hepatocellular carcinoma, cholangiocarcinoma and the rare hepatocellular cholangiocarcinoma (mixed tumor). The indications for liver transplantation and the oncological prognosis differ considerably between these tumor entities. Treatment and decision making for these tumors are often complicated by an underlying chronic liver disease. The aim of this review is to delineate the indications for transplantation and bridging therapies for each cancer entity as well as to highlight some aspects pertinent to transplantation, such as the principles of organ allocation.

[Technical aspects of laparoscopic liver surgery : Transfer from open to laparoscopic liver surgery]. / Technische Aspekte der laparoskopischen Leberchirurgie : Transfer von der offenen zur laparoskopischen Leberchirurgie.

BACKGROUND: Laparoscopic surgery has become the standard for most visceral surgery procedures in many hospitals. Now, liver resections are also being increasingly carried out laparoscopically. The advantages of the laparoscopic technique have been demonstrated in numerous case series and in a recent randomized controlled trial. AIMS: The aim of this review article is to present the available techniques for laparoscopic liver surgery (LLS). METHODS: The technical variations reported in the literature as well as the own experience with LLS are reported. RESULTS: Optimal patient and trocar positions are crucial for successful LLS and they are chosen according to the planned type of liver surgery: the literature offers several options in particular for surgery of the cranial and dorsal liver segments. As for open liver surgery, a restrictive volume management and the application of the Pringle maneuver are helpful to reduce intraoperative blood loss in LLS. In addition, several dissection techniques have been adopted from open liver surgery. The Cavitron Ultrasound Surgical Aspirator (CUSA™) is particularly suitable for parenchymal dissection close to major vascular structures, since it guarantees a meticulous parenchymal dissection with minimal vascular injuries. CONCLUSION: The developments of minimally invasive surgery nowadays allow complex liver resections, which can mostly be performed comparable to open liver surgery. Hopefully, minimally invasive liver surgery will further develop in Germany in the near future, since it offers several advantages over open liver surgery.

Flexible enzymatic activation of artificial polyketide extender units by Streptomyces cinnamonensis into the monensin biosynthetic pathway.

Streptomyces cinnamonensis A495 is a variant of the monensin producer which instead of the native polyether antibiotic gives rise to antibiotic and anti-tumour shunt-product premonensin. Through the supplementation of the fermentation medium with suitable precursors, premonensin can be derivatized via the incorporation of new-to-nature extender units into the biosynthetic machinery. Polyketide extender units require activation, typically in form of coenzyme A-thioesters. These are membrane impermeable and thus in the past an artificial mimic was employed. Here, we show the use and preliminary characterization of a highly substrate promiscuous new enzyme for the endogenous thioester formation in a Streptomyces strain. These intracellularly activated alternative extender units are significantly better incorporated into premonensin than the synthetically activated counterparts. SIGNIFICANCE AND IMPACT OF THE STUDY: Polyketide natural products are of enormous relevance in medicine. The hit-rate in finding active compounds for the potential treatment of various diseases among this substance family of microbial origin is high. However, most polyketides require derivatization to render them suitable for the application. Of relevance in this field is the incorporation of artificial substances into the biogenesis of polyketides, hampered by both the microbial metabolism and the complexity of the enzymes involved. This manuscript describes the straightforward and selective biosynthetic incorporation of synthetic substances into a reduced polyketide and showcases a promising new enzyme to aid this purpose.

Climate deteriorations and Neanderthal demise in interior Iberia.

Time and circumstances for the disappearance of Neanderthals and its relationship with the advent of Modern Humans are not yet sufficiently resolved, especially in case of the Iberian Peninsula. Reconstructing palaeoenvironmental conditions during the last glacial period is crucial to clarifying whether climate deteriorations or competition and contacts with Modern Humans played the pivotal role in driving Neanderthals to extinction. A high-resolution loess record from the Upper Tagus Basin in central Spain demonstrates that the Neanderthal abandonment of inner Iberian territories 42 kyr ago coincided with the evolvement of hostile environmental conditions, while archaeological evidence testifies that this desertion took place regardless of modern humans' activities. According to stratigraphic findings and stable isotope analyses, this period corresponded to the driest environmental conditions of the last glacial apart from an even drier period linked to Heinrich Stadial 3. Our results show that during Marine Isotope Stages (MIS) 4 and 2 climate deteriorations in interior Iberia temporally coincided with northern hemisphere cold periods (Heinrich stadials). Solely during the middle MIS 3, in a period surrounding 42 kyr ago, this relation seems not straightforward, which may demonstrate the complexity of terrestrial climate conditions during glacial periods.