Archaeological evidence of an ethnographically documented Australian Aboriginal ritual dated to the last ice age.

In societies without writing, ethnographically known rituals have rarely been tracked back archaeologically more than a few hundred years. At the invitation of GunaiKurnai Aboriginal Elders, we undertook archaeological excavations at Cloggs Cave in the foothills of the Australian Alps. In GunaiKurnai Country, caves were not used as residential places during the early colonial period (mid-nineteenth century CE), but as secluded retreats for the performance of rituals by Aboriginal medicine men and women known as 'mulla-mullung', as documented by ethnographers. Here we report the discovery of buried 11,000- and 12,000-year-old miniature fireplaces with protruding trimmed wooden artefacts made of Casuarina wood smeared with animal or human fat, matching the configuration and contents of GunaiKurnai ritual installations described in nineteenth-century ethnography. These findings represent 500 generations of cultural transmission of an ethnographically documented ritual practice that dates back to the end of the last ice age and that contains Australia's oldest known wooden artefacts.

Nobody's land? The oldest evidence of early Upper Paleolithic settlements in inland Iberia.

The Iberian Peninsula is a key region for unraveling human settlement histories of Eurasia during the period spanning the decline of Neandertals and the emergence of anatomically modern humans (AMH). There is no evidence of human occupation in central Iberia after the disappearance of Neandertals ~42,000 years ago until approximately 26,000 years ago, rendering the region "nobody's land" during the Aurignacian period. The Abrigo de la Malia provides irrefutable evidence of human settlements dating back to 36,200 to 31,760 calibrated years before the present (cal B.P.) This site also records additional levels of occupation around 32,420 to 26,260 cal B.P., suggesting repeated settlement of this territory. Our multiproxy examination identifies a change in climate trending toward colder and more arid conditions. However, this climatic deterioration does not appear to have affected AMH subsistence strategies or their capacity to inhabit this region. These findings reveal the ability of AMH groups to colonize regions hitherto considered uninhabitable, reopening the debate on early Upper Paleolithic population dynamics of southwestern Europe.

Discovery of KIN-3248, An Irreversible, Next Generation FGFR Inhibitor for the Treatment of Advanced Tumors Harboring FGFR2 and/or FGFR3 Gene Alterations.

Fibroblast growth factor receptor (FGFR) alterations are present as oncogenic drivers and bypass mechanisms in many forms of cancer. These alterations can include fusions, amplifications, rearrangements, and mutations. Acquired drug resistance to current FGFR inhibitors often results in disease progression and unfavorable outcomes for patients. Genomic profiling of tumors refractory to current FGFR inhibitors in the clinic has revealed several acquired driver alterations that could be the target of next generation therapeutics. Herein, we describe how structure-based drug design (SBDD) was used to enable the discovery of the potent and kinome selective pan-FGFR inhibitor KIN-3248, which is active against many acquired resistance mutations. KIN-3248 is currently in phase I clinical development for the treatment of advanced tumors harboring FGFR2 and/or FGFR3 gene alterations.

The Discovery of Exarafenib (KIN-2787): Overcoming the Challenges of Pan-RAF Kinase Inhibition.

RAF, a core signaling component of the MAPK kinase cascade, is often mutated in various cancers, including melanoma, lung, and colorectal cancers. The approved inhibitors were focused on targeting the BRAFV600E mutation that results in constitutive activation of kinase signaling through the monomeric protein (Class I). However, these inhibitors also paradoxically activate kinase signaling of RAF dimers, resulting in increased MAPK signaling in normal tissues. Recently, significant attention has turned to targeting RAF alterations that activate dimeric signaling (class II and III BRAF and NRAS). However, the discovery of a potent and selective inhibitor with biopharmaceutical properties suitable to sustain robust target inhibition in the clinical setting has proven challenging. Herein, we report the discovery of exarafenib (15), a highly potent and selective inhibitor that intercepts the RAF protein in the dimer compatible αC-helix-IN conformation and demonstrates anti-tumor efficacy in preclinical models with BRAF class I, II, and III and NRAS alterations.

Evaluation of in vitro antiviral activity of SARS-CoV-2 Mpro inhibitor pomotrelvir and cross-resistance to nirmatrelvir resistance substitutions.

The unprecedented scale of the COVID-19 pandemic and the rapid evolution of SARS-CoV-2 variants underscore the need for broadly active inhibitors with a high barrier to resistance. The coronavirus main protease (Mpro) is an essential cysteine protease required for viral polyprotein processing and is highly conserved across human coronaviruses. Pomotrelvir is a novel Mpro inhibitor that has recently completed a phase 2 clinical trial. In this report, we demonstrated that pomotrelvir is a potent competitive inhibitor of SARS-CoV-2 Mpro with high selectivity against human proteases. In the enzyme assay, pomotrelvir is also active against Mpro proteins derived from human coronaviruses CoV-229E, CoV-OC43, CoV-HKU1, CoV-NL63, MERS, and SARS-CoV. In cell-based SARS-CoV-2 replicon and SARS-CoV-2 infection assays, pomotrelvir has shown potent inhibitory activity and is broadly active against SARS-CoV-2 clinical isolates including Omicron variants. Many resistance substitutions of the Mpro inhibitor nirmatrelvir confer cross-resistance to pomotrelvir, consistent with the finding from our enzymatic analysis that pomotrelvir and nirmatrelvir compete for the same binding site. In a SARS-CoV-2 infection assay, pomotrelvir is additive when combined with remdesivir or molnupiravir, two nucleoside analogs targeting viral RNA synthesis. In conclusion, our results from the in vitro characterization of pomotrelvir antiviral activity support its further clinical development as an alternative COVID-19 therapeutic option.

Ulnar Wrist Denervation: Articular Branching Pattern and Selective Blockade of the Dorsal Branch of the Ulnar Nerve.

PURPOSE: Ulnar wrist denervation has been a successful treatment for patients with ulnar-sided wrist pain. The purpose of this study was to characterize the articular branches of the dorsal branch of the ulnar nerve (DBUN) and validate a technique for selective peripheral nerve blockade. METHODS: In cadavers, we performed simulated local anesthetic injections using 0.5 mL of 0.5% methylene into the subcutaneous tissue at a point midway between the palpable borders of the pisiform and ulnar styloid. We then dissected the DBUN, characterized its articular branching pattern, and measured staining intensity of the DBUN and the ulnar nerve relative to a standard. RESULTS: The DBUN branched from the ulnar nerve 7.0 ± 1.2 cm proximal to the ulnar styloid. Among 17 specimens, the DBUN provided an average of 1.2 (range, 0-2) ulnocarpal branches and 1.0 (range, 0-2) carpometacarpal articular branches. A simulated local anesthetic injection successfully stained 100% of the DBUN articular branches at or proximal to their takeoff. There was no staining of the proper ulnar nerves. In all specimens, the DBUN supplied at least one articular branch. CONCLUSIONS: A point midway between the palpable border of the pisiform and ulnar styloid may be an effective location for selectively blocking the DBUN articular afferents. CLINICAL RELEVANCE: In this study, we were able to identify a point halfway between the pisiform and ulnar styloid that has the potential to produce a selective peripheral nerve block of the portion of the DBUN that supplies articular fibers to the ulnocarpal joint and the fifth carpometacarpal joint. This technique may prove useful to surgeons treating ulnar-sided wrist pain.

A marine isotope stage 13 Acheulian sequence from the Amanzi Springs Area 2 Deep Sounding excavation, Eastern Cape, South Africa.

Renewed research at Amanzi Springs has increased resolution on the timing and technology of the Acheulian industry in South Africa. The archeology from the Area 1 spring eye has recently been dated to MIS 11 (∼404-390 ka), and analyses revealed significant technological variability when compared to other southern African Acheulian assemblages. We expand on these results in presenting new luminescence dating and technological analyses of Acheulian stone tools from three artifact-bearing surfaces exposed within the White Sands unit of the Deep Sounding excavation in the Area 2 spring eye. The two lowest surfaces (Surfaces 3 and 2) are sealed within the White Sands and dated between ∼534 to 496 ka and ∼496 to 481 ka (MIS 13), respectively. Surface 1 represents materials deflated onto an erosional surface that cut the upper part of the White Sands (∼481 ka; late MIS 13), which occurred before the deposition of younger Cutting 5 sediments (<408-<290 ka; MIS 11-8). Archaeological comparisons reveal that the older Surface 3 and 2 assemblages are predominated by unifacial and bifacial core reduction and relatively thick, cobble-reduced large cutting tools. In contrast, the younger Surface 1 assemblage is characterized by discoidal core reduction and thinner large cutting tools, mostly made from flake blanks. Typological similarities between the older Area 2 White Sands and younger Area 1 (404-390 ka; MIS 11) assemblages further suggest long-term continuity in site function. We hypothesize Amanzi Springs represent a workshop locality that Acheulian hominins repeatedly visited to access unique floral, faunal, and raw material resources from at least ∼534 to 390 ka.

A marine isotope stage 11 coastal Acheulian workshop with associated wood at Amanzi Springs Area 1, South Africa.

Amanzi Springs is a series of inactive thermal springs located near Kariega in the Eastern Cape of South Africa. Excavations in the 1960s exposed rare, stratified Acheulian-bearing deposits that were not further investigated over the next 50 years. Reanalysis of the site and its legacy collection has led to a redefined stratigraphic context for the archaeology, a confirmed direct association between Acheulian artefacts and wood, as well as the first reliable age estimates for the site. Thermally transferred optically stimulated luminescence and post-infrared infrared stimulated luminescence dating indicates that the Acheulian deposits from the Amanzi Springs Area 1 spring eye formed during Marine Isotope Stage (MIS) 11 at ~ 404-390 ka. At this time, higher sea levels of ~13-14m would have placed Amanzi Springs around 7 km from a ria that would have formed along what is today the Swartkops River, and which likely led to spring reactivation. This makes the Amanzi Springs Area 1 assemblage an unusual occurrence of a verified late occurring, seaward, open-air Acheulian occupation. The Acheulian levels do not contain any Middle Stone Age (MSA) elements such as blades and points that have been documented in the interior of South Africa at this time. However, a small number of stone tools from the upper layers of the artefact zone, and originally thought of as intrusive, have been dated to ~190 ka, at the transition between MIS 7 to 6, and represent the first potential MSA identified at the site.

The intrusive nature of the Châtelperronian in the Iberian Peninsula.

Multiple factors have been proposed to explain the disappearance of Neandertals between ca. 50 and 40 kyr BP. Central to these discussions has been the identification of new techno-cultural complexes that overlap with the period of Neandertal demise in Europe. One such complex is the Châtelperronian, which extends from the Paris Basin to the Northern Iberian Peninsula between 43,760-39,220 BP. In this study we present the first open-air Châtelperronian site in the Northern Iberian Peninsula, Aranbaltza II. The technological features of its stone tool assemblage show no links with previous Middle Paleolithic technology in the region, and chronological modeling reveals a gap between the latest Middle Paleolithic and the Châtelperronian in this area. We interpret this as evidence of local Neandertal extinction and replacement by other Neandertal groups coming from southern France, illustrating how local extinction episodes could have played a role in the process of disappearance of Neandertals.

Modern human incursion into Neanderthal territories 54,000 years ago at Mandrin, France.

Determining the extent of overlap between modern humans and other hominins in Eurasia, such as Neanderthals and Denisovans, is fundamental to understanding the nature of their interactions and what led to the disappearance of archaic hominins. Apart from a possible sporadic pulse recorded in Greece during the Middle Pleistocene, the first settlements of modern humans in Europe have been constrained to ~45,000 to 43,000 years ago. Here, we report hominin fossils from Grotte Mandrin in France that reveal the earliest known presence of modern humans in Europe between 56,800 and 51,700 years ago. This early modern human incursion in the Rhône Valley is associated with technologies unknown in any industry of that age outside Africa or the Levant. Mandrin documents the first alternating occupation of Neanderthals and modern humans, with a modern human fossil and associated Neronian lithic industry found stratigraphically between layers containing Neanderthal remains associated with Mousterian industries.

Revisiting the Middle and Upper Palaeolithic archaeology of Gruta do Caldeirão (Tomar, Portugal).

Gruta do Caldeirão features a c. 6 m-thick archaeological stratification capped by Holocene layers ABC-D and Ea, which overlie layer Eb, a deposit of Magdalenian age that underwent significant disturbance, intrusion, and component mixing caused by funerary use of the cave during the Early Neolithic. Here, we provide an updated overview of the stratigraphy and archaeological content of the underlying Pleistocene succession, whose chronology we refine using radiocarbon and single-grain optically stimulated luminescence dating. We find a high degree of stratigraphic integrity. Dating anomalies exist in association with the succession's two major discontinuities: between layer Eb and Upper Solutrean layer Fa, and between Early Upper Palaeolithic layer K and Middle Palaeolithic layer L. Mostly, the anomalies consist of older-than-expected radiocarbon ages and can be explained by bioturbation and palimpsest-forming sedimentation hiatuses. Combined with palaeoenvironmental inferences derived from magnetic susceptibility analyses, the dating shows that sedimentation rates varied in tandem with the oscillations in global climate revealed by the Greenland oxygen isotope record. A steep increase in sedimentation rate is observed through the Last Glacial Maximum, resulting in a c. 1.5 m-thick accumulation containing conspicuous remains of occupation by people of the Solutrean technocomplex, whose traditional subdivision is corroborated: the index fossils appear in the expected stratigraphic order; the diagnostics of the Protosolutrean and the Lower Solutrean predate 24,000 years ago; and the constraints on the Upper Solutrean place it after Greenland Interstadial 2.2. (23,220-23,340 years ago). Human usage of the site during the Early Upper and the Middle Palaeolithic is episodic and low-intensity: stone tools are few, and the faunal remains relate to carnivore activity. The Middle Palaeolithic is found to persist beyond 39,000 years ago, at least three millennia longer than in the Franco-Cantabrian region. This conclusion is upheld by Bayesian modelling and stands even if the radiocarbon ages for the Middle Palaeolithic levels are removed from consideration (on account of observed inversions and the method's potential for underestimation when used close to its limit of applicability). A number of localities in Spain and Portugal reveal a similar persistence pattern. The key evidence comes from high-resolution fluviatile contexts spared by the site formation issues that our study of Caldeirão brings to light-palimpsest formation, post-depositional disturbance, and erosion. These processes. are ubiquitous in the cave and rock-shelter sites of Iberia, reflecting the impact on karst archives of the variation in climate and environments that occurred through the Upper Pleistocene, and especially at two key points in time: between 37,000 and 42,000 years ago, and after the Last Glacial Maximum. Such empirical difficulties go a long way towards explaining the controversies surrounding the associated cultural transitions: from the Middle to the Upper Palaeolithic, and from the Solutrean to the Magdalenian. Alongside potential dating error caused by incomplete decontamination, proper consideration of sample association issues is required if we are ever to fully understand what happened with the human settlement of Iberia during these critical intervals, and especially so with regards to the fate of Iberia's last Neandertal populations.

Relief of Sitting Pain by Resecting Posterior Femoral Cutaneous Nerve, and Elucidation of Its Anatomical Branching Pattern.

BACKGROUND: Injury to the posterior femoral cutaneous nerve (PFCN) produces sitting pain in the buttock, posterior thigh, and/or the ischial tuberosity. The anatomy of the PFCN has not been well described, and just one small cohort of patients has been reported to have resection of the PFCN. METHODS: Retrospective review of all patients undergoing resection of the PFCN for sitting pain by the senior author between 2012 and 2019 was performed. Evaluation was done by chart review, intraoperative description of the anatomy of the PFCN, and the outcome of resection of the PFCN with implantation of the proximal nerve into the gluteus muscle. Outcome was determined by direct patient examination, email reports, and telephonic interview. RESULTS: Fifty-two patients were included in this study, of which nine were bilateral operative procedures. Thirty-four patients had sufficient follow-up data at a mean of 23 months (3-85 months, range). MRI evidence of hamstring injury was present in 50% of the patients. The classic PFCN anatomy was present in 44% of limbs with the other 56% having a high division permitting branches to the lateral buttock and posterior thigh to be preserved. In patients with bilateral anatomy observations, symmetry was present in 67%. An excellent result (absence of sitting pain, normal activities of daily living [ADL]) was obtained in 53%, a good result (some residual sitting pain with some reduction in ADL), was obtained in 26% and no improvement was observed in 21% of patients. CONCLUSION: Sitting pain due to injury to the PFCN can be relieved by the resection of the PFCN with implantation of the proximal end into muscle. Presence of an anatomical variation, a high division of the PFCN, can permit preservation of sensation in the lateral buttock and posterior thigh in the patient whose symptoms involve just the perineum and ischial tuberosity.

Examining Neanderthal and carnivore occupations of Teixoneres Cave (Moià, Barcelona, Spain) using archaeostratigraphic and intra-site spatial analysis.

Teixoneres Cave (Moià, Barcelona, Spain) is a reference site for Middle Palaeolithic studies of the Iberian Peninsula. The cave preserves an extensive stratigraphic sequence made up of eight units, which is presented in depth in this work. The main goal of this study is to undertake an initial spatial examination of Unit III, formed during Marine Isotope Stage 3, with the aim of understanding spatial organization and past activities developed by Neanderthals and carnivores (bears, hyenas and smaller carnivores). The total sample analysed includes 38,244 archaeological items and 5888 limestone blocks. The application of GIS tools allows us to clearly distinguish three geologically-defined stratigraphic subunits. Unit III has been previously interpreted as a palimpsest resulting from alternating occupation of the cave by human groups and carnivores. The distribution study shows that faunal specimens, lithic artefacts, hearths and charcoal fragments are significantly concentrated at the entrance of the cave where, it is inferred, hominins carried out different activities, while carnivores preferred the sheltered zones in the inner areas of the cave. The results obtained reveal a spatial pattern characterized by fire use related zones, and show that the site was occupied by Neanderthals in a similar and consistent way throughout the ˃ 7000 years range covered by the analysed subunits. This spatial pattern is interpreted as resulting from repeated short-term human occupations.

2000 Year-old Bogong moth (Agrotis infusa) Aboriginal food remains, Australia.

Insects form an important source of food for many people around the world, but little is known of the deep-time history of insect harvesting from the archaeological record. In Australia, early settler writings from the 1830s to mid-1800s reported congregations of Aboriginal groups from multiple clans and language groups taking advantage of the annual migration of Bogong moths (Agrotis infusa) in and near the Australian Alps, the continent's highest mountain range. The moths were targeted as a food item for their large numbers and high fat contents. Within 30 years of initial colonial contact, however, the Bogong moth festivals had ceased until their recent revival. No reliable archaeological evidence of Bogong moth exploitation or processing has ever been discovered, signalling a major gap in the archaeological history of Aboriginal groups. Here we report on microscopic remains of ground and cooked Bogong moths on a recently excavated grindstone from Cloggs Cave, in the southern foothills of the Australian Alps. These findings represent the first conclusive archaeological evidence of insect foods in Australia, and, as far as we know, of their remains on stone artefacts in the world. They provide insights into the antiquity of important Aboriginal dietary practices that have until now remained archaeologically invisible.

Hepatitis B virus Core protein nuclear interactome identifies SRSF10 as a host RNA-binding protein restricting HBV RNA production.

Despite the existence of a preventive vaccine, chronic infection with Hepatitis B virus (HBV) affects more than 250 million people and represents a major global cause of hepatocellular carcinoma (HCC) worldwide. Current clinical treatments, in most of cases, do not eliminate viral genome that persists as a DNA episome in the nucleus of hepatocytes and constitutes a stable template for the continuous expression of viral genes. Several studies suggest that, among viral factors, the HBV core protein (HBc), well-known for its structural role in the cytoplasm, could have critical regulatory functions in the nucleus of infected hepatocytes. To elucidate these functions, we performed a proteomic analysis of HBc-interacting host-factors in the nucleus of differentiated HepaRG, a surrogate model of human hepatocytes. The HBc interactome was found to consist primarily of RNA-binding proteins (RBPs), which are involved in various aspects of mRNA metabolism. Among them, we focused our studies on SRSF10, a RBP that was previously shown to regulate alternative splicing (AS) in a phosphorylation-dependent manner and to control stress and DNA damage responses, as well as viral replication. Functional studies combining SRSF10 knockdown and a pharmacological inhibitor of SRSF10 phosphorylation (1C8) showed that SRSF10 behaves as a restriction factor that regulates HBV RNAs levels and that its dephosphorylated form is likely responsible for the anti-viral effect. Surprisingly, neither SRSF10 knock-down nor 1C8 treatment modified the splicing of HBV RNAs but rather modulated the level of nascent HBV RNA. Altogether, our work suggests that in the nucleus of infected cells HBc interacts with multiple RBPs that regulate viral RNA metabolism. Our identification of SRSF10 as a new anti-HBV restriction factor offers new perspectives for the development of new host-targeted antiviral strategies.

Risk Factors Associated With the Progression From Acute to Chronic Neuropathic Pain After Burn-Related Injuries.

BACKGROUND: Pain, unrelated to the initial thermal trauma itself, can result after burn injury and prolong the recovery/rehabilitation phase of the patient's care. This pain, after discharge from the burn unit, may be acute and self-limiting or chronic and contribute to long-term patient morbidity. The purposes of this study were to compare burn patients who had, after discharge from the burn unit, only acute pain with burn patients who developed chronic, neuropathic pain (CNP) and to determine risks factors for progression from acute to chronic pain in the setting of a burn center. METHODS: A single-center, retrospective chart review of patients admitted to the adult burn center was performed from January 1, 2014, to January 1, 2019. Patients included were older than 15 years, sustained a burn injury, and admitted to the burn unit. Chronic pain was defined as pain lasting greater than 6 months after discharge from the burn unit. Pain descriptors included shooting, stabbing, sharp, burning, tingling, numbness, throbbing, pruritus, intermittent, and/or continuous dysesthetic sensations after the burn. Patients were excluded if they had preexisting neuropathic pain due to an underlying medical illness or previous surgery. RESULTS: During a 5-year period, of the 1880 admissions to the burn unit, 143 burn patients developed post-initial-onset pain as a direct result of their burn. Of the 143 patients with acute pain, pain resolved in 30 patients, whereas pain progressed to CNP in 113 patients (79%). Patient follow-up was a median (interquartile range [IQR]) of 26.5 (10-45) months. Patients whose pain progressed to CNP had significantly greater percent total body surface area burns (median [IQR], 6 [3-25] vs 3 [1-10]; P = 0.032), had more full-thickness burns (66/113 [58%] vs 8/30 [27%] patients, P = 0.004), had surgery (85/113 [75%] vs 16/30 [53%] patients, P = 0.042), had more surgical procedures (median [IQR], 2 [1-6] vs 1 [0-3], P = 0.002), and developed more complications (32/113 [28%] vs 2/30 [7%] patients, P = 0.014) compared with those with acute neuropathic pain, respectively. CONCLUSIONS: Burn patients who progressed from having acute to CNP had significantly greater percent total body surface area burns, had more full-thickness burns, had surgery, had more surgical procedures, and developed more complications compared with burn patients with only acute pain.

Extinction of eastern Sahul megafauna coincides with sustained environmental deterioration.

Explanations for the Upper Pleistocene extinction of megafauna from Sahul (Australia and New Guinea) remain unresolved. Extinction hypotheses have advanced climate or human-driven scenarios, in spite of over three quarters of Sahul lacking reliable biogeographic or chronologic data. Here we present new megafauna from north-eastern Australia that suffered extinction sometime after 40,100 (±1700) years ago. Megafauna fossils preserved alongside leaves, seeds, pollen and insects, indicate a sclerophyllous forest with heathy understorey that was home to aquatic and terrestrial carnivorous reptiles and megaherbivores, including the world's largest kangaroo. Megafauna species diversity is greater compared to southern sites of similar age, which is contrary to expectations if extinctions followed proposed migration routes for people across Sahul. Our results do not support rapid or synchronous human-mediated continental-wide extinction, or the proposed timing of peak extinction events. Instead, megafauna extinctions coincide with regionally staggered spatio-temporal deterioration in hydroclimate coupled with sustained environmental change.

Publisher Correction: First experimental evaluation of the alpha efficiency in coarse-grained quartz for ESR dating purposes: implications for dose rate evaluation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Bladder Pain Syndome/Interstitial Cystitis due to Pudendal Nerve Compression: Described in 1915-A Reminder for Treating Pelvic Pain a Century Later.

Background Interstitial cystitis (IC) or bladder pain syndrome (BPS) is highly painful and disabling and probably the most misdiagnosed urologic condition. Its classic symptoms of perineal pain, urinary urgency, and frequency despite sterile urine cultures were already described more than a century ago in a report on soldiers during World War (WW) I due to chronic pudendal nerve compression. Objectives This article translates a report from 1915 on pudendal neuropathy and discusses its author Georg Zülzer (1870-1949). Methods An English translation of the German original is provided with the biography and work of Zülzer, his clinical observations are discussed regarding modern diagnosis and therapy of pudendal nerve compression. Results In his article entitled "Irritation of the Pudendal Nerve (Neuralgia). A Frequent Clinical Picture during War Feigning Bladder Catarrh," Zülzer describes his observation of soldiers during WW I, presenting with a triad of perineal pain, urinary urgency, and frequency despite sterile urine cultures excluding urinary infections. He also documented a characteristic skin hypersensibility of the perineum in a rhomboid shape which corresponds to the innervation area of the pudendal nerve with its two branches deriving from the "pudendal plexus." He regards this symptomology as rare during peace, but as disease of trench warfare which can be easily diagnosed regarding clear urine and a painful skin island overlying the area of the pudendal nerve as tested by simple needle examination. Zülzer, born in Germany, was forced to emigrate to the United States in 1934, was also an important pioneer of diabetes research using pancreas extracts from dogs as early as 1907. Conclusion In this historical description, dating from about a century ago, Georg Zülzer probably gave the first exact clinical description of symptoms due to pudendal nerve compression. Pudendal nerve compression should always be taken into account when examining and treating patients with symptoms of IC/BPS.